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Q15858

- SCN9A_HUMAN

UniProt

Q15858 - SCN9A_HUMAN

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Protein

Sodium channel protein type 9 subunit alpha

Gene

SCN9A

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na+ ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-sensitive Na+ channel isoform. Plays a role in pain mechanisms, especially in the development of inflammatory pain (By similarity).By similarity

GO - Molecular functioni

  1. sodium ion binding Source: Ensembl
  2. voltage-gated sodium channel activity Source: RefGenome

GO - Biological processi

  1. behavioral response to pain Source: Ensembl
  2. inflammatory response Source: Ensembl
  3. membrane depolarization during action potential Source: RefGenome
  4. neuronal action potential Source: RefGenome
  5. post-embryonic development Source: Ensembl
  6. response to toxic substance Source: Ensembl
  7. sodium ion transmembrane transport Source: RefGenome
  8. sodium ion transport Source: ProtInc
Complete GO annotation...

Keywords - Molecular functioni

Ion channel, Sodium channel, Voltage-gated channel

Keywords - Biological processi

Ion transport, Sodium transport, Transport

Keywords - Ligandi

Sodium

Enzyme and pathway databases

ReactomeiREACT_22266. Interaction between L1 and Ankyrins.

Protein family/group databases

TCDBi1.A.1.10.5. the voltage-gated ion channel (vic) superfamily.

Names & Taxonomyi

Protein namesi
Recommended name:
Sodium channel protein type 9 subunit alpha
Alternative name(s):
Neuroendocrine sodium channel
Short name:
hNE-Na
Peripheral sodium channel 1
Short name:
PN1
Sodium channel protein type IX subunit alpha
Voltage-gated sodium channel subunit alpha Nav1.7
Gene namesi
Name:SCN9A
Synonyms:NENA
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 2

Organism-specific databases

HGNCiHGNC:10597. SCN9A.

Subcellular locationi

Membrane; Multi-pass membrane protein
Note: In neurite terminals.By similarity

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei122 – 14524Helical; Name=S1 of repeat ISequence AnalysisAdd
BLAST
Transmembranei154 – 17320Helical; Name=S2 of repeat ISequence AnalysisAdd
BLAST
Transmembranei187 – 20519Helical; Name=S3 of repeat ISequence AnalysisAdd
BLAST
Transmembranei212 – 23120Helical; Voltage-sensor; Name=S4 of repeat ISequence AnalysisAdd
BLAST
Transmembranei248 – 27124Helical; Name=S5 of repeat ISequence AnalysisAdd
BLAST
Transmembranei379 – 40426Helical; Name=S6 of repeat ISequence AnalysisAdd
BLAST
Transmembranei739 – 76325Helical; Name=S1 of repeat IISequence AnalysisAdd
BLAST
Transmembranei775 – 79824Helical; Name=S2 of repeat IISequence AnalysisAdd
BLAST
Transmembranei807 – 82620Helical; Name=S3 of repeat IISequence AnalysisAdd
BLAST
Transmembranei833 – 85220Helical; Voltage-sensor; Name=S4 of repeat IISequence AnalysisAdd
BLAST
Transmembranei869 – 88921Helical; Name=S5 of repeat IISequence AnalysisAdd
BLAST
Transmembranei943 – 96826Helical; Name=S6 of repeat IISequence AnalysisAdd
BLAST
Transmembranei1188 – 121124Helical; Name=S1 of repeat IIISequence AnalysisAdd
BLAST
Transmembranei1225 – 125026Helical; Name=S2 of repeat IIISequence AnalysisAdd
BLAST
Transmembranei1257 – 127822Helical; Name=S3 of repeat IIISequence AnalysisAdd
BLAST
Transmembranei1283 – 130422Helical; Voltage-sensor; Name=S4 of repeat IIISequence AnalysisAdd
BLAST
Transmembranei1324 – 135128Helical; Name=S5 of repeat IIISequence AnalysisAdd
BLAST
Transmembranei1431 – 145727Helical; Name=S6 of repeat IIISequence AnalysisAdd
BLAST
Transmembranei1511 – 153424Helical; Name=S1 of repeat IVSequence AnalysisAdd
BLAST
Transmembranei1546 – 156924Helical; Name=S2 of repeat IVSequence AnalysisAdd
BLAST
Transmembranei1576 – 159924Helical; Name=S3 of repeat IVSequence AnalysisAdd
BLAST
Transmembranei1610 – 163122Helical; Voltage-sensor; Name=S4 of repeat IVSequence AnalysisAdd
BLAST
Transmembranei1647 – 166923Helical; Name=S5 of repeat IVSequence AnalysisAdd
BLAST
Transmembranei1736 – 176025Helical; Name=S6 of repeat IVSequence AnalysisAdd
BLAST

GO - Cellular componenti

  1. plasma membrane Source: RefGenome
  2. voltage-gated sodium channel complex Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Involvement in diseasei

Primary erythermalgia (PERYTHM) [MIM:133020]: Autosomal dominant disease characterized by recurrent episodes of severe pain associated with redness and warmth in the feet or hands.6 Publications
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti10 – 101Q → R in PERYTHM; causes a hyperpolarizing shift of -5.3 mV for the midpoint of activation which is smaller than that seen in other mutations causing early-onset erythromelalgia mutations; also causes a faster rate of activation and slower deactivation compared to wild-type; expression of the mutant protein induced hyperexcitability in dorsal root ganglion neurons but the increase is smaller than that produced by Thr-859. 1 Publication
VAR_064595
Natural varianti216 – 2161F → S in PERYTHM; hyperpolarizes the voltage dependence of activation by 11 mV, accelerates activation, slows deactivation and enhances the response to slow, small depolarizations. 1 Publication
VAR_064598
Natural varianti241 – 2411S → T in PERYTHM. 1 Publication
VAR_032014
Natural varianti395 – 3951N → K in PERYTHM. 1 Publication
VAR_064600
Natural varianti406 – 4061E → K in PERYTHM.
VAR_064601
Natural varianti859 – 8591I → T in PERYTHM; sporadic; activated at more negative potentials; slower inactivation kinetics than wild-type channels. 2 Publications
VAR_019947
Natural varianti869 – 8691L → F in PERYTHM; causes a hyperpolarizing shift in channel activation, a depolarizing shift of inactivation and an 18-fold increase in deactivation time compared to wild-type; the mean ramp current amplitude in response to slow depolarization is higher in the mutant channels. 2 Publications
VAR_064609
Natural varianti869 – 8691L → H in PERYTHM; activated at more negative potentials; slower inactivation kinetics than wild-type channels. 1 Publication
VAR_019948
Natural varianti1460 – 14601F → V in PERYTHM; produces a hyperpolarizing shift in channel activation and a depolarizing shift in steady-state activation. 1 Publication
VAR_032019
Congenital indifference to pain autosomal recessive (CIPAR) [MIM:243000]: A disorder characterized by congenital inability to perceive any form of pain, in any part of the body. All other sensory modalities are preserved and the peripheral and central nervous systems are apparently intact. Patients perceive the sensations of touch, warm and cold temperature, proprioception, tickle and pressure, but not painful stimuli. There is no evidence of a motor or sensory neuropathy, either axonal or demyelinating.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti907 – 9071R → Q in CIPAR; significant reduction in membrane localization of the mutant protein compared to the wild-type; complete loss of function of the sodium channel. 1 Publication
VAR_064610
Natural varianti1381 – 13855Missing in CIPAR; significant reduction in membrane localization of the mutant protein compared to the wild-type; complete loss of function of the sodium channel. 1 Publication
VAR_064614
Paroxysmal extreme pain disorder (PEPD) [MIM:167400]: Autosomal dominant paroxysmal disorder of pain and autonomic dysfunction. The distinctive features are paroxysmal episodes of burning pain in the rectal, ocular, and mandibular areas accompanied by autonomic manifestations such as skin flushing.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti1007 – 10071R → C in PEPD. 1 Publication
Corresponds to variant rs121908910 [ dbSNP | Ensembl ].
VAR_032015
Natural varianti1309 – 13091V → D in PEPD. 1 Publication
VAR_032016
Natural varianti1309 – 13091V → F in PEPD. 1 Publication
VAR_032017
Natural varianti1310 – 13101V → F in PEPD. 1 Publication
VAR_032018
Natural varianti1472 – 14721I → T in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 Publication
VAR_032020
Natural varianti1473 – 14731F → V in PEPD. 1 Publication
VAR_032021
Natural varianti1475 – 14751T → I in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 Publication
VAR_032022
Natural varianti1638 – 16381M → K in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 Publication
VAR_032023
Generalized epilepsy with febrile seizures plus 7 (GEFS+7) [MIM:613863]: A rare autosomal dominant, familial condition with incomplete penetrance and large intrafamilial variability. Patients display febrile seizures persisting sometimes beyond the age of 6 years and/or a variety of afebrile seizure types. This disease combines febrile seizures, generalized seizures often precipitated by fever at age 6 years or more, and partial seizures, with a variable degree of severity.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti641 – 6411N → Y in GEFS+7. 1 Publication
VAR_064604
Natural varianti666 – 6661K → R in GEFS+7; also found in a patient with severe myoclonic epilepsy in infancy. 1 Publication
Corresponds to variant rs121908919 [ dbSNP | Ensembl ].
VAR_064605
Febrile seizures, familial, 3B (FEB3B) [MIM:613863]: Seizures associated with febrile episodes in childhood without any evidence of intracranial infection or defined pathologic or traumatic cause. It is a common condition, affecting 2-5% of children aged 3 months to 5 years. The majority are simple febrile seizures (generally defined as generalized onset, single seizures with a duration of less than 30 minutes). Complex febrile seizures are characterized by focal onset, duration greater than 30 minutes, and/or more than one seizure in a 24 hour period. The likelihood of developing epilepsy following simple febrile seizures is low. Complex febrile seizures are associated with a moderately increased incidence of epilepsy.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti62 – 621I → V in FEB3B. 1 Publication
VAR_064596
Natural varianti149 – 1491P → Q in FEB3B. 1 Publication
VAR_064597

Keywords - Diseasei

Disease mutation, Epilepsy

Organism-specific databases

MIMi133020. phenotype.
167400. phenotype.
243000. phenotype.
613863. phenotype.
Orphaneti88642. Channelopathy-associated congenital insensitivity to pain.
33069. Dravet syndrome.
1956. Erythromelalgia.
36387. Generalized epilepsy with febrile seizures-plus.
970. Hereditary sensory and autonomic neuropathy type 2.
46348. Paroxysmal extreme pain disorder.
90026. Primary erythermalgia.
306577. Sodium channelopathy-related small fiber neuropathy.
PharmGKBiPA35010.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 19881988Sodium channel protein type 9 subunit alphaPRO_0000048502Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi209 – 2091N-linked (GlcNAc...)Sequence Analysis
Glycosylationi283 – 2831N-linked (GlcNAc...)Sequence Analysis
Glycosylationi1352 – 13521N-linked (GlcNAc...)Sequence Analysis
Glycosylationi1366 – 13661N-linked (GlcNAc...)Sequence Analysis
Glycosylationi1375 – 13751N-linked (GlcNAc...)Sequence Analysis
Modified residuei1490 – 14901Phosphoserine; by PKCBy similarity

Post-translational modificationi

Ubiquitinated by NEDD4L; which may promote its endocytosis. Does not seem to be ubiquitinated by NEDD4 (By similarity).By similarity
Phosphorylation at Ser-1490 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents.By similarity

Keywords - PTMi

Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ15858.
PRIDEiQ15858.

PTM databases

PhosphoSiteiQ15858.

Expressioni

Tissue specificityi

Expressed strongly in dorsal root ganglion, with only minor levels elsewhere in the body, smooth muscle cells, MTC cell line and C-cell carcinoma. Isoform 1 is expressed preferentially in the central and peripheral nervous system. Isoform 2 is expressed preferentially in the dorsal root ganglion.4 Publications

Gene expression databases

BgeeiQ15858.
CleanExiHS_SCN9A.
ExpressionAtlasiQ15858. baseline and differential.
GenevestigatoriQ15858.

Organism-specific databases

HPAiCAB013679.

Interactioni

Subunit structurei

The sodium channel consists of a large polypeptide and 2-3 smaller ones. This sequence represents a large polypeptide. Interacts with NEDD4 and NEDD4L (By similarity).By similarity

Structurei

3D structure databases

ProteinModelPortaliQ15858.
SMRiQ15858. Positions 1761-1913.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Repeati121 – 405285IAdd
BLAST
Repeati738 – 969232IIAdd
BLAST
Repeati1187 – 1458272IIIAdd
BLAST
Repeati1510 – 1761252IVAdd
BLAST
Domaini1889 – 191830IQAdd
BLAST

Domaini

The sequence contains 4 internal repeats, each with 5 hydrophobic segments (S1,S2,S3,S5,S6) and one positively charged segment (S4). Segments S4 are probably the voltage-sensors and are characterized by a series of positively charged amino acids at every third position.

Sequence similaritiesi

Contains 1 IQ domain.Curated

Keywords - Domaini

Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG1226.
GeneTreeiENSGT00760000118827.
HOVERGENiHBG053100.
InParanoidiQ15858.
KOiK04841.
OrthoDBiEOG7DJSK9.
PhylomeDBiQ15858.
TreeFamiTF323985.

Family and domain databases

Gene3Di1.20.120.350. 4 hits.
InterProiIPR027359. Channel_four-helix_dom.
IPR024583. DUF3451.
IPR005821. Ion_trans_dom.
IPR000048. IQ_motif_EF-hand-BS.
IPR001696. Na_channel_asu.
IPR010526. Na_trans_assoc.
IPR028803. SCN9A.
[Graphical view]
PANTHERiPTHR10037:SF28. PTHR10037:SF28. 1 hit.
PfamiPF11933. DUF3451. 1 hit.
PF00520. Ion_trans. 4 hits.
PF06512. Na_trans_assoc. 1 hit.
[Graphical view]
PRINTSiPR00170. NACHANNEL.
SMARTiSM00015. IQ. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: Q15858-1) [UniParc]FASTAAdd to Basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAMLPPPGPQ SFVHFTKQSL ALIEQRIAER KSKEPKEEKK DDDEEAPKPS
60 70 80 90 100
SDLEAGKQLP FIYGDIPPGM VSEPLEDLDP YYADKKTFIV LNKGKTIFRF
110 120 130 140 150
NATPALYMLS PFSPLRRISI KILVHSLFSM LIMCTILTNC IFMTMNNPPD
160 170 180 190 200
WTKNVEYTFT GIYTFESLVK ILARGFCVGE FTFLRDPWNW LDFVVIVFAY
210 220 230 240 250
LTEFVNLGNV SALRTFRVLR ALKTISVIPG LKTIVGALIQ SVKKLSDVMI
260 270 280 290 300
LTVFCLSVFA LIGLQLFMGN LKHKCFRNSL ENNETLESIM NTLESEEDFR
310 320 330 340 350
KYFYYLEGSK DALLCGFSTD SGQCPEGYTC VKIGRNPDYG YTSFDTFSWA
360 370 380 390 400
FLALFRLMTQ DYWENLYQQT LRAAGKTYMI FFVVVIFLGS FYLINLILAV
410 420 430 440 450
VAMAYEEQNQ ANIEEAKQKE LEFQQMLDRL KKEQEEAEAI AAAAAEYTSI
460 470 480 490 500
RRSRIMGLSE SSSETSKLSS KSAKERRNRR KKKNQKKLSS GEEKGDAEKL
510 520 530 540 550
SKSESEDSIR RKSFHLGVEG HRRAHEKRLS TPNQSPLSIR GSLFSARRSS
560 570 580 590 600
RTSLFSFKGR GRDIGSETEF ADDEHSIFGD NESRRGSLFV PHRPQERRSS
610 620 630 640 650
NISQASRSPP MLPVNGKMHS AVDCNGVVSL VDGRSALMLP NGQLLPEVII
660 670 680 690 700
DKATSDDSGT TNQIHKKRRC SSYLLSEDML NDPNLRQRAM SRASILTNTV
710 720 730 740 750
EELEESRQKC PPWWYRFAHK FLIWNCSPYW IKFKKCIYFI VMDPFVDLAI
760 770 780 790 800
TICIVLNTLF MAMEHHPMTE EFKNVLAIGN LVFTGIFAAE MVLKLIAMDP
810 820 830 840 850
YEYFQVGWNI FDSLIVTLSL VELFLADVEG LSVLRSFRLL RVFKLAKSWP
860 870 880 890 900
TLNMLIKIIG NSVGALGNLT LVLAIIVFIF AVVGMQLFGK SYKECVCKIN
910 920 930 940 950
DDCTLPRWHM NDFFHSFLIV FRVLCGEWIE TMWDCMEVAG QAMCLIVYMM
960 970 980 990 1000
VMVIGNLVVL NLFLALLLSS FSSDNLTAIE EDPDANNLQI AVTRIKKGIN
1010 1020 1030 1040 1050
YVKQTLREFI LKAFSKKPKI SREIRQAEDL NTKKENYISN HTLAEMSKGH
1060 1070 1080 1090 1100
NFLKEKDKIS GFGSSVDKHL MEDSDGQSFI HNPSLTVTVP IAPGESDLEN
1110 1120 1130 1140 1150
MNAEELSSDS DSEYSKVRLN RSSSSECSTV DNPLPGEGEE AEAEPMNSDE
1160 1170 1180 1190 1200
PEACFTDGCV WRFSCCQVNI ESGKGKIWWN IRKTCYKIVE HSWFESFIVL
1210 1220 1230 1240 1250
MILLSSGALA FEDIYIERKK TIKIILEYAD KIFTYIFILE MLLKWIAYGY
1260 1270 1280 1290 1300
KTYFTNAWCW LDFLIVDVSL VTLVANTLGY SDLGPIKSLR TLRALRPLRA
1310 1320 1330 1340 1350
LSRFEGMRVV VNALIGAIPS IMNVLLVCLI FWLIFSIMGV NLFAGKFYEC
1360 1370 1380 1390 1400
INTTDGSRFP ASQVPNRSEC FALMNVSQNV RWKNLKVNFD NVGLGYLSLL
1410 1420 1430 1440 1450
QVATFKGWTI IMYAAVDSVN VDKQPKYEYS LYMYIYFVVF IIFGSFFTLN
1460 1470 1480 1490 1500
LFIGVIIDNF NQQKKKLGGQ DIFMTEEQKK YYNAMKKLGS KKPQKPIPRP
1510 1520 1530 1540 1550
GNKIQGCIFD LVTNQAFDIS IMVLICLNMV TMMVEKEGQS QHMTEVLYWI
1560 1570 1580 1590 1600
NVVFIILFTG ECVLKLISLR HYYFTVGWNI FDFVVVIISI VGMFLADLIE
1610 1620 1630 1640 1650
TYFVSPTLFR VIRLARIGRI LRLVKGAKGI RTLLFALMMS LPALFNIGLL
1660 1670 1680 1690 1700
LFLVMFIYAI FGMSNFAYVK KEDGINDMFN FETFGNSMIC LFQITTSAGW
1710 1720 1730 1740 1750
DGLLAPILNS KPPDCDPKKV HPGSSVEGDC GNPSVGIFYF VSYIIISFLV
1760 1770 1780 1790 1800
VVNMYIAVIL ENFSVATEES TEPLSEDDFE MFYEVWEKFD PDATQFIEFS
1810 1820 1830 1840 1850
KLSDFAAALD PPLLIAKPNK VQLIAMDLPM VSGDRIHCLD ILFAFTKRVL
1860 1870 1880 1890 1900
GESGEMDSLR SQMEERFMSA NPSKVSYEPI TTTLKRKQED VSATVIQRAY
1910 1920 1930 1940 1950
RRYRLRQNVK NISSIYIKDG DRDDDLLNKK DMAFDNVNEN SSPEKTDATS
1960 1970 1980
STTSPPSYDS VTKPDKEKYE QDRTEKEDKG KDSKESKK
Length:1,988
Mass (Da):226,372
Last modified:April 5, 2011 - v3
Checksum:i1BAEB8F32EBF5438
GO
Isoform 2 (identifier: Q15858-2) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     200-229: YLTEFVNLGNVSALRTFRVLRALKTISVIP → YVTEFVDLGNVSALRTFRVLRALKTISVIP

Show »
Length:1,988
Mass (Da):226,359
Checksum:i8C9066AD56148C02
GO
Isoform 3 (identifier: Q15858-3) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     648-658: Missing.

Show »
Length:1,977
Mass (Da):225,227
Checksum:i8B2BD5CF665F11A8
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti201 – 2011L → V in AAT85835. (PubMed:15302875)Curated
Sequence conflicti201 – 2011L → V in AAT85833. (PubMed:15302875)Curated
Sequence conflicti206 – 2061N → D in AAT85835. (PubMed:15302875)Curated
Sequence conflicti206 – 2061N → D in AAT85833. (PubMed:15302875)Curated
Sequence conflicti267 – 2671F → S in AAT85834. (PubMed:15302875)Curated
Sequence conflicti301 – 3011K → R in AAT85835. (PubMed:15302875)Curated
Sequence conflicti309 – 3091S → P in AAT85834. (PubMed:15302875)Curated
Sequence conflicti420 – 4201E → G in AAT85834. (PubMed:15302875)Curated
Sequence conflicti430 – 4301L → P in AAT85834. (PubMed:15302875)Curated
Sequence conflicti501 – 5011S → P in AAT85835. (PubMed:15302875)Curated
Sequence conflicti610 – 6101P → T in AAT85835. (PubMed:15302875)Curated
Sequence conflicti642 – 6421G → R in AAT85835. (PubMed:15302875)Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti10 – 101Q → R in PERYTHM; causes a hyperpolarizing shift of -5.3 mV for the midpoint of activation which is smaller than that seen in other mutations causing early-onset erythromelalgia mutations; also causes a faster rate of activation and slower deactivation compared to wild-type; expression of the mutant protein induced hyperexcitability in dorsal root ganglion neurons but the increase is smaller than that produced by Thr-859. 1 Publication
VAR_064595
Natural varianti62 – 621I → V in FEB3B. 1 Publication
VAR_064596
Natural varianti149 – 1491P → Q in FEB3B. 1 Publication
VAR_064597
Natural varianti216 – 2161F → S in PERYTHM; hyperpolarizes the voltage dependence of activation by 11 mV, accelerates activation, slows deactivation and enhances the response to slow, small depolarizations. 1 Publication
VAR_064598
Natural varianti228 – 2281I → M.1 Publication
Corresponds to variant rs71428908 [ dbSNP | Ensembl ].
VAR_064599
Natural varianti241 – 2411S → T in PERYTHM. 1 Publication
VAR_032014
Natural varianti395 – 3951N → K in PERYTHM. 1 Publication
VAR_064600
Natural varianti406 – 4061E → K in PERYTHM.
VAR_064601
Natural varianti490 – 4901S → N.1 Publication
Corresponds to variant rs58022607 [ dbSNP | Ensembl ].
VAR_064602
Natural varianti519 – 5191E → K.1 Publication
Corresponds to variant rs187453572 [ dbSNP | Ensembl ].
VAR_064603
Natural varianti641 – 6411N → Y in GEFS+7. 1 Publication
VAR_064604
Natural varianti666 – 6661K → R in GEFS+7; also found in a patient with severe myoclonic epilepsy in infancy. 1 Publication
Corresponds to variant rs121908919 [ dbSNP | Ensembl ].
VAR_064605
Natural varianti695 – 6951I → M.1 Publication
VAR_064606
Natural varianti710 – 7101C → Y Found in a patient with severe myoclonic epilepsy in infancy. 1 Publication
VAR_064607
Natural varianti750 – 7501I → V.1 Publication
Corresponds to variant rs182650126 [ dbSNP | Ensembl ].
VAR_064608
Natural varianti859 – 8591I → T in PERYTHM; sporadic; activated at more negative potentials; slower inactivation kinetics than wild-type channels. 2 Publications
VAR_019947
Natural varianti869 – 8691L → F in PERYTHM; causes a hyperpolarizing shift in channel activation, a depolarizing shift of inactivation and an 18-fold increase in deactivation time compared to wild-type; the mean ramp current amplitude in response to slow depolarization is higher in the mutant channels. 2 Publications
VAR_064609
Natural varianti869 – 8691L → H in PERYTHM; activated at more negative potentials; slower inactivation kinetics than wild-type channels. 1 Publication
VAR_019948
Natural varianti907 – 9071R → Q in CIPAR; significant reduction in membrane localization of the mutant protein compared to the wild-type; complete loss of function of the sodium channel. 1 Publication
VAR_064610
Natural varianti932 – 9321M → L.
Corresponds to variant rs12478318 [ dbSNP | Ensembl ].
VAR_030444
Natural varianti943 – 9431M → L.
Corresponds to variant rs12478318 [ dbSNP | Ensembl ].
VAR_055646
Natural varianti1007 – 10071R → C in PEPD. 1 Publication
Corresponds to variant rs121908910 [ dbSNP | Ensembl ].
VAR_032015
Natural varianti1134 – 11341L → F.1 Publication
Corresponds to variant rs200160858 [ dbSNP | Ensembl ].
VAR_064611
Natural varianti1161 – 11611W → R.3 Publications
Corresponds to variant rs6746030 [ dbSNP | Ensembl ].
VAR_019949
Natural varianti1171 – 11711E → Q Found in a patient with severe myoclonic epilepsy in infancy. 1 Publication
VAR_064612
Natural varianti1278 – 12781L → V.1 Publication
Corresponds to variant rs180922748 [ dbSNP | Ensembl ].
VAR_064613
Natural varianti1309 – 13091V → D in PEPD. 1 Publication
VAR_032016
Natural varianti1309 – 13091V → F in PEPD. 1 Publication
VAR_032017
Natural varianti1310 – 13101V → F in PEPD. 1 Publication
VAR_032018
Natural varianti1381 – 13855Missing in CIPAR; significant reduction in membrane localization of the mutant protein compared to the wild-type; complete loss of function of the sodium channel. 1 Publication
VAR_064614
Natural varianti1460 – 14601F → V in PERYTHM; produces a hyperpolarizing shift in channel activation and a depolarizing shift in steady-state activation. 1 Publication
VAR_032019
Natural varianti1472 – 14721I → T in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 Publication
VAR_032020
Natural varianti1473 – 14731F → V in PEPD. 1 Publication
VAR_032021
Natural varianti1475 – 14751T → I in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 Publication
VAR_032022
Natural varianti1638 – 16381M → K in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 Publication
VAR_032023
Natural varianti1919 – 19191D → G.
Corresponds to variant rs3750904 [ dbSNP | Ensembl ].
VAR_019950

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei200 – 22930YLTEF…ISVIP → YVTEFVDLGNVSALRTFRVL RALKTISVIP in isoform 2. 1 PublicationVSP_012028Add
BLAST
Alternative sequencei648 – 65811Missing in isoform 3. 3 PublicationsVSP_012029Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X82835 mRNA. Translation: CAA58042.1.
DQ857292 mRNA. Translation: ABI51981.1.
AC074101 Genomic DNA. No translation available.
AC107082 Genomic DNA. No translation available.
AC108146 Genomic DNA. No translation available.
AY682084 mRNA. Translation: AAT85833.1.
AY682085 mRNA. Translation: AAT85834.1.
AY682086 mRNA. Translation: AAT85835.1.
AJ310882 mRNA. Translation: CAC84550.1.
AJ310883 mRNA. Translation: CAC84551.1.
AJ310897 mRNA. Translation: CAC84537.1.
AJ580918 Genomic DNA. Translation: CAE45644.1.
AJ580919 Genomic DNA. Translation: CAE45645.1.
CCDSiCCDS46441.1. [Q15858-3]
PIRiS54771.
RefSeqiNP_002968.1. NM_002977.3.
XP_005246814.1. XM_005246757.1. [Q15858-1]
UniGeneiHs.439145.

Genome annotation databases

EnsembliENST00000303354; ENSP00000304748; ENSG00000169432. [Q15858-1]
ENST00000409435; ENSP00000386330; ENSG00000169432. [Q15858-1]
ENST00000409672; ENSP00000386306; ENSG00000169432. [Q15858-3]
ENST00000454569; ENSP00000413212; ENSG00000169432.
GeneIDi6335.
KEGGihsa:6335.
UCSCiuc010fpl.3. human. [Q15858-3]

Polymorphism databases

DMDMi327478559.

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

Wikipedia

SCN9A entry

Protein Spotlight

Silent pain - Issue 102 of February 2009

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X82835 mRNA. Translation: CAA58042.1 .
DQ857292 mRNA. Translation: ABI51981.1 .
AC074101 Genomic DNA. No translation available.
AC107082 Genomic DNA. No translation available.
AC108146 Genomic DNA. No translation available.
AY682084 mRNA. Translation: AAT85833.1 .
AY682085 mRNA. Translation: AAT85834.1 .
AY682086 mRNA. Translation: AAT85835.1 .
AJ310882 mRNA. Translation: CAC84550.1 .
AJ310883 mRNA. Translation: CAC84551.1 .
AJ310897 mRNA. Translation: CAC84537.1 .
AJ580918 Genomic DNA. Translation: CAE45644.1 .
AJ580919 Genomic DNA. Translation: CAE45645.1 .
CCDSi CCDS46441.1. [Q15858-3 ]
PIRi S54771.
RefSeqi NP_002968.1. NM_002977.3.
XP_005246814.1. XM_005246757.1. [Q15858-1 ]
UniGenei Hs.439145.

3D structure databases

ProteinModelPortali Q15858.
SMRi Q15858. Positions 1761-1913.
ModBasei Search...
MobiDBi Search...

Chemistry

BindingDBi Q15858.
ChEMBLi CHEMBL4296.
DrugBanki DB06218. Lacosamide.
DB00281. Lidocaine.
DB00243. Ranolazine.
DB06201. Rufinamide.
DB00313. Valproic Acid.
DB00909. Zonisamide.
GuidetoPHARMACOLOGYi 584.

Protein family/group databases

TCDBi 1.A.1.10.5. the voltage-gated ion channel (vic) superfamily.

PTM databases

PhosphoSitei Q15858.

Polymorphism databases

DMDMi 327478559.

Proteomic databases

PaxDbi Q15858.
PRIDEi Q15858.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000303354 ; ENSP00000304748 ; ENSG00000169432 . [Q15858-1 ]
ENST00000409435 ; ENSP00000386330 ; ENSG00000169432 . [Q15858-1 ]
ENST00000409672 ; ENSP00000386306 ; ENSG00000169432 . [Q15858-3 ]
ENST00000454569 ; ENSP00000413212 ; ENSG00000169432 .
GeneIDi 6335.
KEGGi hsa:6335.
UCSCi uc010fpl.3. human. [Q15858-3 ]

Organism-specific databases

CTDi 6335.
GeneCardsi GC02M167051.
GeneReviewsi SCN9A.
HGNCi HGNC:10597. SCN9A.
HPAi CAB013679.
MIMi 133020. phenotype.
167400. phenotype.
243000. phenotype.
603415. gene.
613863. phenotype.
neXtProti NX_Q15858.
Orphaneti 88642. Channelopathy-associated congenital insensitivity to pain.
33069. Dravet syndrome.
1956. Erythromelalgia.
36387. Generalized epilepsy with febrile seizures-plus.
970. Hereditary sensory and autonomic neuropathy type 2.
46348. Paroxysmal extreme pain disorder.
90026. Primary erythermalgia.
306577. Sodium channelopathy-related small fiber neuropathy.
PharmGKBi PA35010.
GenAtlasi Search...

Phylogenomic databases

eggNOGi COG1226.
GeneTreei ENSGT00760000118827.
HOVERGENi HBG053100.
InParanoidi Q15858.
KOi K04841.
OrthoDBi EOG7DJSK9.
PhylomeDBi Q15858.
TreeFami TF323985.

Enzyme and pathway databases

Reactomei REACT_22266. Interaction between L1 and Ankyrins.

Miscellaneous databases

GeneWikii Nav1.7.
GenomeRNAii 6335.
NextBioi 24600.
PROi Q15858.
SOURCEi Search...

Gene expression databases

Bgeei Q15858.
CleanExi HS_SCN9A.
ExpressionAtlasi Q15858. baseline and differential.
Genevestigatori Q15858.

Family and domain databases

Gene3Di 1.20.120.350. 4 hits.
InterProi IPR027359. Channel_four-helix_dom.
IPR024583. DUF3451.
IPR005821. Ion_trans_dom.
IPR000048. IQ_motif_EF-hand-BS.
IPR001696. Na_channel_asu.
IPR010526. Na_trans_assoc.
IPR028803. SCN9A.
[Graphical view ]
PANTHERi PTHR10037:SF28. PTHR10037:SF28. 1 hit.
Pfami PF11933. DUF3451. 1 hit.
PF00520. Ion_trans. 4 hits.
PF06512. Na_trans_assoc. 1 hit.
[Graphical view ]
PRINTSi PR00170. NACHANNEL.
SMARTi SM00015. IQ. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells."
    Klugbauer N., Lacinova L., Flockerzi V., Hofmann F.
    EMBO J. 14:1084-1090(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION IN VOLTAGE-EVOKED DEPOLARIZATION, TISSUE SPECIFICITY, VARIANT ARG-1161.
    Tissue: Thyroid.
  2. Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), INVOLVEMENT IN CONGENITAL INSENSITIVITY TO PAIN, CHARACTERIZATION, VARIANT ARG-1161.
  3. "Generation and annotation of the DNA sequences of human chromosomes 2 and 4."
    Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H.
    , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.
    Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. "Expression of alternatively spliced sodium channel alpha-subunit genes: unique splicing patterns are observed in dorsal root ganglia."
    Raymond C.K., Castle J.C., Garrett-Engele P.W., Armour C.D., Kan Z.G., Tsinoremas N.T., Johnson J.M.
    J. Biol. Chem. 279:46234-46241(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 136-674 (ISOFORMS 1; 2 AND 3), TISSUE SPECIFICITY.
    Tissue: Spinal ganglion.
  5. "Upregulation of voltage-gated Na+ channel expression and metastatic potential in human breast cancer: correlative studies on cell lines and biopsy tissues."
    Diss J.K.J., Fraser S.P., Coombes R.C., Djamgoz M.B.A.
    Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 150-264 AND 1340-1400.
  6. "Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia."
    Yang Y., Wang Y., Li S., Xu Z., Li H., Ma L., Fan J., Bu D., Liu B., Fan Z., Wu G., Jin J., Ding B., Zhu X., Shen Y.
    J. Med. Genet. 41:171-174(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 840-958, VARIANTS PERYTHM THR-859 AND HIS-869.
  7. Cited for: TISSUE SPECIFICITY.
  8. "Voltage-gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A."
    Jo T., Nagata T., Iida H., Imuta H., Iwasawa K., Ma J., Hara K., Omata M., Nagai R., Takizawa H., Nagase T., Nakajima T.
    FEBS Lett. 567:339-343(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN VOLTAGE-EVOKED DEPOLARIZATION, TISSUE SPECIFICITY.
  9. "Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy."
    Cummins T.R., Dib-Hajj S.D., Waxman S.G.
    J. Neurosci. 24:8232-8236(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: CHARACTERIZATION OF VARIANTS PERYTHM THR-859 AND HIS-869.
  10. "Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7."
    Michiels J.J., te Morsche R.H.M., Jansen J.B.M.J., Drenth J.P.H.
    Arch. Neurol. 62:1587-1590(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PERYTHM THR-241.
  11. "Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons."
    Dib-Hajj S.D., Rush A.M., Cummins T.R., Hisama F.M., Novella S., Tyrrell L., Marshall L., Waxman S.G.
    Brain 128:1847-1854(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PERYTHM VAL-1460, CHARACTERIZATION OF VARIANT PERYTHM VAL-1460.
  12. "SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels."
    Drenth J.P., te Morsche R.H., Guillet G., Taieb A., Kirby R.L., Jansen J.B.
    J. Invest. Dermatol. 124:1333-1338(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANTS PERYTHM SER-216; LYS-395; THR-859 AND PHE-869, VARIANT ARG-1161.
  13. "Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7."
    Han C., Rush A.M., Dib-Hajj S.D., Li S., Xu Z., Wang Y., Tyrrell L., Wang X., Yang Y., Waxman S.G.
    Ann. Neurol. 59:553-558(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PERYTHM PHE-869, CHARACTERIZATION OF VARIANT PERYTHM PHE-869.
  14. "Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy."
    Choi J.S., Dib-Hajj S.D., Waxman S.G.
    Neurology 67:1563-1567(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: CHARACTERIZATION OF VARIANT PERYTHM SER-216.
  15. "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes."
    Fertleman C.R., Baker M.D., Parker K.A., Moffatt S., Elmslie F.V., Abrahamsen B., Ostman J., Klugbauer N., Wood J.N., Gardiner R.M., Rees M.
    Neuron 52:767-774(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANTS PEPD CYS-1007; PHE-1309; ASP-1309; PHE-1310; THR-1472; VAL-1473; ILE-1475 AND LYS-1638, CHARACTERIZATION OF VARIANTS PEPD THR-1472; ILE-1475 AND LYS-1638.
  16. "A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons."
    Rush A.M., Dib-Hajj S.D., Liu S., Cummins T.R., Black J.A., Waxman S.G.
    Proc. Natl. Acad. Sci. U.S.A. 103:8245-8250(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: CHARACTERIZATION OF VARIANT PERYTHM HIS-869.
  17. "Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation."
    Han C., Dib-Hajj S.D., Lin Z., Li Y., Eastman E.M., Tyrrell L., Cao X., Yang Y., Waxman S.G.
    Brain 132:1711-1722(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PERYTHM ARG-10, CHARACTERIZATION OF VARIANTS PERYTHM ARG-10 AND THR-859.
  18. "A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome."
    Singh N.A., Pappas C., Dahle E.J., Claes L.R., Pruess T.H., De Jonghe P., Thompson J., Dixon M., Gurnett C., Peiffer A., White H.S., Filloux F., Leppert M.F.
    PLoS Genet. 5:E1000649-E1000649(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANTS GEFS+7 TYR-641 AND ARG-666, VARIANTS FEB3B VAL-62 AND GLN-149, VARIANTS MET-228; ASN-490; LYS-519; MET-695; TYR-710; VAL-750; PHE-1134; GLN-1171 AND VAL-1278.
  19. "Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations."
    Cox J.J., Sheynin J., Shorer Z., Reimann F., Nicholas A.K., Zubovic L., Baralle M., Wraige E., Manor E., Levy J., Woods C.G., Parvari R.
    Hum. Mutat. 31:E1670-E1686(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANTS CIPAR GLN-907 AND 1381-ARG--LEU-1385 DEL, CHARACTERIZATION OF VARIANTS CIPAR GLN-907 AND 1381-ARG--LEU-1385 DEL.

Entry informationi

Entry nameiSCN9A_HUMAN
AccessioniPrimary (citable) accession number: Q15858
Secondary accession number(s): A1BUH5
, Q6B4R9, Q6B4S0, Q6B4S1, Q70HX1, Q70HX2, Q8WTU1, Q8WWN4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 23, 2004
Last sequence update: April 5, 2011
Last modified: October 29, 2014
This is version 136 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Protein Spotlight
    Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3