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Protein

Vitamin K epoxide reductase complex subunit 1

Gene

VKORC1

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

Functioni

Involved in vitamin K metabolism. Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin K 2,3-epoxide to active vitamin K. Vitamin K is required for the gamma-carboxylation of various proteins, including clotting factors, and is required for normal blood coagulation, but also for normal bone development.6 Publications

Catalytic activityi

Phylloquinone + oxidized dithiothreitol + H2O = 2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol.4 Publications

Enzyme regulationi

Inhibited by warfarin (coumadin).3 Publications

GO - Molecular functioni

  • quinone binding Source: UniProtKB-KW
  • vitamin-K-epoxide reductase (warfarin-sensitive) activity Source: UniProtKB

GO - Biological processi

  • blood coagulation Source: UniProtKB
  • bone development Source: UniProtKB
  • drug metabolic process Source: UniProtKB
  • peptidyl-glutamic acid carboxylation Source: UniProtKB
  • vitamin K metabolic process Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Oxidoreductase

Enzyme and pathway databases

BioCyciZFISH:HS15548-MONOMER.
BRENDAi1.1.4.1. 2681.
ReactomeiR-HSA-6806664. Metabolism of vitamin K.

Names & Taxonomyi

Protein namesi
Recommended name:
Vitamin K epoxide reductase complex subunit 1 (EC:1.17.4.44 Publications)
Alternative name(s):
Vitamin K1 2,3-epoxide reductase subunit 1
Gene namesi
Name:VKORC1
Synonyms:VKOR
ORF Names:MSTP134, MSTP576, UNQ308/PRO351
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 16

Organism-specific databases

HGNCiHGNC:23663. VKORC1.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 8LumenalSequence analysis8
Transmembranei9 – 29HelicalCuratedAdd BLAST21
Topological domaini30 – 74CytoplasmicSequence analysisAdd BLAST45
Transmembranei75 – 95HelicalSequence analysisAdd BLAST21
Transmembranei101 – 123HelicalCuratedAdd BLAST23
Topological domaini124 – 126LumenalCurated3
Transmembranei127 – 149HelicalCuratedAdd BLAST23
Topological domaini150 – 163CytoplasmicCuratedAdd BLAST14

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Involvement in diseasei

Combined deficiency of vitamin K-dependent clotting factors 2 (VKCFD2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionVKCFD leads to a bleeding tendency that is usually reversed by oral administration of vitamin K.
See also OMIM:607473
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02182498R → W in VKCFD2; strongly reduced enzyme activity. 2 PublicationsCorresponds to variant rs72547528dbSNPEnsembl.1
Coumarin resistance (CMRES)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA condition characterized by partial or complete resistance to warfarin or other 4-hydroxycoumarin derivatives. These drugs are used as anti-coagulants for the prevention of thromboembolic diseases in subjects with deep vein thrombosis, atrial fibrillation, or mechanical heart valve replacement.
See also OMIM:122700
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06578526A → T in CMRES. 1 Publication1
Natural variantiVAR_02182129V → L in CMRES. 2 PublicationsCorresponds to variant rs104894539dbSNPEnsembl.1
Natural variantiVAR_06578636D → G in CMRES. 1 Publication1
Natural variantiVAR_06578736D → Y in CMRES. 1 PublicationCorresponds to variant rs61742245dbSNPEnsembl.1
Natural variantiVAR_02182245V → A in CMRES. 1 PublicationCorresponds to variant rs104894540dbSNPEnsembl.1
Natural variantiVAR_06578852S → W in CMRES. 1 Publication1
Natural variantiVAR_06578956S → F in CMRES. 1 Publication1
Natural variantiVAR_02182358R → G in CMRES. 1 PublicationCorresponds to variant rs104894541dbSNPEnsembl.1
Natural variantiVAR_06579059W → C in CMRES. 1 Publication1
Natural variantiVAR_06579159W → L in CMRES. 1 Publication1
Natural variantiVAR_06579266V → G in CMRES. 1 Publication1
Natural variantiVAR_06579366V → M in CMRES. 1 PublicationCorresponds to variant rs72547529dbSNPEnsembl.1
Natural variantiVAR_06579471G → A in CMRES. 1 Publication1
Natural variantiVAR_06579577N → S in CMRES. 1 Publication1
Natural variantiVAR_06579677N → Y in CMRES. 1 PublicationCorresponds to variant rs755767348dbSNPEnsembl.1
Natural variantiVAR_065797123I → N in CMRES. 1 Publication1
Natural variantiVAR_021825128L → R in CMRES. 1 PublicationCorresponds to variant rs104894542dbSNPEnsembl.1
Natural variantiVAR_065798139Y → H in CMRES. 1 Publication1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi16C → A or S: Reduces enzyme activity by about 80%. 1 Publication1
Mutagenesisi35R → P: Nearly abolishes enzyme activity. 1 Publication1
Mutagenesisi43C → A or S: Reduces enzyme activity. 2 Publications1
Mutagenesisi51C → A or S: Reduces enzyme activity. 2 Publications1
Mutagenesisi56S → P: Nearly abolishes enzyme activity. 1 Publication1
Mutagenesisi57S → A: Nearly abolishes enzyme activity. 1 Publication1
Mutagenesisi85C → A: Reduces enzyme activity by about 25%. 1 Publication1
Mutagenesisi85C → S: Reduces enzyme activity by about 75%. 1 Publication1
Mutagenesisi96C → A or S: Reduces enzyme activity by about 70%. 1 Publication1
Mutagenesisi98R → D or E: Reduces enzyme activity by about 80%. Decreases inhibition by warfarin. 1 Publication1
Mutagenesisi98R → K: No effect on enzyme activity. Decreases inhibition by warfarin. 1 Publication1
Mutagenesisi120L → Q: Decreases enzyme activity moderately. Decreases inhibition by warfarin. 1 Publication1
Mutagenesisi128L → Q or S: Decreases enzyme activity by about 80%. Decreases inhibition by warfarin. 1 Publication1
Mutagenesisi132C → S: Nearly abolishes enzyme activity. 1 Publication1
Mutagenesisi135C → S: Nearly abolishes enzyme activity. 1 Publication1
Mutagenesisi139Y → C, G or S: Decreases enzyme activity moderately. Strongly decreases inhibition by warfarin. 2 Publications1
Mutagenesisi139Y → F: No effect on enzyme activity. Strongly decreases inhibition by warfarin. 2 Publications1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi79001.
MalaCardsiVKORC1.
MIMi122700. phenotype.
607473. phenotype.
OpenTargetsiENSG00000167397.
Orphaneti98434. Hereditary combined deficiency of vitamin K-dependent clotting factors.
413684. Resistance to vitamin K antagonists.
413674. Vitamin K antagonists toxicity or dose selection.
PharmGKBiPA133787052.

Chemistry databases

ChEMBLiCHEMBL1930.
DrugBankiDB01418. Acenocoumarol.
DB00266. Dicoumarol.
DB00170. Menadione.
DB00498. Phenindione.
DB00946. Phenprocoumon.
DB00682. Warfarin.
GuidetoPHARMACOLOGYi2645.

Polymorphism and mutation databases

BioMutaiVKORC1.
DMDMi62511226.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001916681 – 163Vitamin K epoxide reductase complex subunit 1Add BLAST163

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi132 ↔ 135Redox-active

Keywords - PTMi

Disulfide bond, Quinone

Proteomic databases

EPDiQ9BQB6.
MaxQBiQ9BQB6.
PaxDbiQ9BQB6.
PeptideAtlasiQ9BQB6.
PRIDEiQ9BQB6.

PTM databases

iPTMnetiQ9BQB6.
PhosphoSitePlusiQ9BQB6.
SwissPalmiQ9BQB6.

Expressioni

Tissue specificityi

Expressed at highest levels in fetal and adult liver, followed by fetal heart, kidney, and lung, adult heart, and pancreas.1 Publication

Gene expression databases

BgeeiENSG00000167397.
CleanExiHS_VKORC1.
ExpressionAtlasiQ9BQB6. baseline and differential.
GenevisibleiQ9BQB6. HS.

Organism-specific databases

HPAiHPA042720.

Interactioni

Protein-protein interaction databases

BioGridi122472. 98 interactors.
IntActiQ9BQB6. 36 interactors.
STRINGi9606.ENSP00000378426.

Chemistry databases

BindingDBiQ9BQB6.

Structurei

3D structure databases

ProteinModelPortaliQ9BQB6.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domaini

The number of transmembrane domains and the membrane topology are controversial; supporting evidence is available both for models with three transmembrane domains (PubMed:15716279 and PubMed:22923610) and four transmembrane domains (PubMed:20696932 and PubMed:20978134). According to PubMed:15716279 and PubMed:22923610 the N-terminus of the protein is in the endoplasmic reticulum lumen, while the C-terminus is in the cytosol, which is in favor of three transmembrane domains. According to PubMed:20696932, both N-terminus and C-terminus are in the cytosol, indicating the presence of four transmembrane domains. Besides, the 3D-structure of a bacterial ortholog shows four transmembrane domains. Moreover, proteins that reside in the endoplasmic reticulum lumen can catalyze the reduction of the active site cysteines, possibly via Cys-43 and Cys-51 (PubMed:20696932 and PubMed:20978134), but less efficiently than the synthetic compound dithiothreitol (in vitro). Location of Cys-43 and Cys-51 in the endoplasmic reticulum lumen would be in agreement with four transmembrane domains. Again, these data are controversial, and papers do not agree on the effects of mutating Cys-43 and Cys-51, probably because of differences in the assay systems.

Sequence similaritiesi

Belongs to the VKOR family.Curated

Keywords - Domaini

Redox-active center, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410J0HT. Eukaryota.
ENOG4111UX7. LUCA.
GeneTreeiENSGT00390000002103.
HOGENOMiHOG000230752.
HOVERGENiHBG076672.
InParanoidiQ9BQB6.
KOiK05357.
OMAiWSSILLV.
OrthoDBiEOG091G0QTR.
PhylomeDBiQ9BQB6.
TreeFamiTF328467.

Family and domain databases

InterProiIPR012932. VKOR.
[Graphical view]
PfamiPF07884. VKOR. 1 hit.
[Graphical view]
SMARTiSM00756. VKc. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9BQB6-1) [UniParc]FASTAAdd to basket
Also known as: MST576

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
MGSTWGSPGW VRLALCLTGL VLSLYALHVK AARARDRDYR ALCDVGTAIS
60 70 80 90 100
CSRVFSSRWG RGFGLVEHVL GQDSILNQSN SIFGCIFYTL QLLLGCLRTR
110 120 130 140 150
WASVLMLLSS LVSLAGSVYL AWILFFVLYD FCIVCITTYA INVSLMWLSF
160
RKVQEPQGKA KRH
Length:163
Mass (Da):18,235
Last modified:June 1, 2001 - v1
Checksum:i2F00526A6C561D5A
GO
Isoform 2 (identifier: Q9BQB6-2) [UniParc]FASTAAdd to basket
Also known as: MST134

The sequence of this isoform differs from the canonical sequence as follows:
     95-163: GCLRTRWASV...QEPQGKAKRH → DGVSPCCPGW...PGLDPVLRAL

Show »
Length:156
Mass (Da):16,701
Checksum:iFBB87922208F471C
GO
Isoform 3 (identifier: Q9BQB6-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     59-163: WGRGFGLVEH...QEPQGKAKRH → LPADTLGLCPDAAELPGVSRWFCLPGLDPVLRAL

Note: No experimental confirmation available.
Show »
Length:92
Mass (Da):9,875
Checksum:iCB4ADA0C5ED486BD
GO

Sequence cautioni

The sequence AAQ88821 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06578526A → T in CMRES. 1 Publication1
Natural variantiVAR_02182129V → L in CMRES. 2 PublicationsCorresponds to variant rs104894539dbSNPEnsembl.1
Natural variantiVAR_06578636D → G in CMRES. 1 Publication1
Natural variantiVAR_06578736D → Y in CMRES. 1 PublicationCorresponds to variant rs61742245dbSNPEnsembl.1
Natural variantiVAR_02182245V → A in CMRES. 1 PublicationCorresponds to variant rs104894540dbSNPEnsembl.1
Natural variantiVAR_06578852S → W in CMRES. 1 Publication1
Natural variantiVAR_06578956S → F in CMRES. 1 Publication1
Natural variantiVAR_02182358R → G in CMRES. 1 PublicationCorresponds to variant rs104894541dbSNPEnsembl.1
Natural variantiVAR_06579059W → C in CMRES. 1 Publication1
Natural variantiVAR_06579159W → L in CMRES. 1 Publication1
Natural variantiVAR_06579266V → G in CMRES. 1 Publication1
Natural variantiVAR_06579366V → M in CMRES. 1 PublicationCorresponds to variant rs72547529dbSNPEnsembl.1
Natural variantiVAR_06579471G → A in CMRES. 1 Publication1
Natural variantiVAR_06579577N → S in CMRES. 1 Publication1
Natural variantiVAR_06579677N → Y in CMRES. 1 PublicationCorresponds to variant rs755767348dbSNPEnsembl.1
Natural variantiVAR_02182498R → W in VKCFD2; strongly reduced enzyme activity. 2 PublicationsCorresponds to variant rs72547528dbSNPEnsembl.1
Natural variantiVAR_065797123I → N in CMRES. 1 Publication1
Natural variantiVAR_021825128L → R in CMRES. 1 PublicationCorresponds to variant rs104894542dbSNPEnsembl.1
Natural variantiVAR_065798139Y → H in CMRES. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_04340759 – 163WGRGF…KAKRH → LPADTLGLCPDAAELPGVSR WFCLPGLDPVLRAL in isoform 3. 1 PublicationAdd BLAST105
Alternative sequenceiVSP_01336395 – 163GCLRT…KAKRH → DGVSPCCPGWSQAICLPQPP KVLGGLQALPADTLGLCPDA AELPGVSRWFCLPGLDPVLR AL in isoform 2. 1 PublicationAdd BLAST69

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY423044 mRNA. Translation: AAR82914.1.
AY521634 mRNA. Translation: AAS01052.1.
AF176924 mRNA. Translation: AAQ13668.1.
AY466113 mRNA. Translation: AAR28759.1.
AY587020 Genomic DNA. Translation: AAS83106.1.
AK289790 mRNA. Translation: BAF82479.1.
AK312005 mRNA. Translation: BAG34943.1.
AC135050 Genomic DNA. No translation available.
CH471192 Genomic DNA. Translation: EAW52167.1.
CH471192 Genomic DNA. Translation: EAW52168.1.
BC002911 mRNA. Translation: AAH02911.1.
AY358456 mRNA. Translation: AAQ88821.1. Different initiation.
CCDSiCCDS10703.1. [Q9BQB6-1]
CCDS10704.1. [Q9BQB6-3]
RefSeqiNP_001298240.1. NM_001311311.1.
NP_076869.1. NM_024006.5. [Q9BQB6-1]
NP_996560.1. NM_206824.2. [Q9BQB6-3]
UniGeneiHs.324844.

Genome annotation databases

EnsembliENST00000319788; ENSP00000326135; ENSG00000167397. [Q9BQB6-2]
ENST00000354895; ENSP00000346969; ENSG00000167397. [Q9BQB6-3]
ENST00000394975; ENSP00000378426; ENSG00000167397. [Q9BQB6-1]
GeneIDi79001.
KEGGihsa:79001.
UCSCiuc002eas.4. human. [Q9BQB6-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Web resourcesi

SeattleSNPs

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY423044 mRNA. Translation: AAR82914.1.
AY521634 mRNA. Translation: AAS01052.1.
AF176924 mRNA. Translation: AAQ13668.1.
AY466113 mRNA. Translation: AAR28759.1.
AY587020 Genomic DNA. Translation: AAS83106.1.
AK289790 mRNA. Translation: BAF82479.1.
AK312005 mRNA. Translation: BAG34943.1.
AC135050 Genomic DNA. No translation available.
CH471192 Genomic DNA. Translation: EAW52167.1.
CH471192 Genomic DNA. Translation: EAW52168.1.
BC002911 mRNA. Translation: AAH02911.1.
AY358456 mRNA. Translation: AAQ88821.1. Different initiation.
CCDSiCCDS10703.1. [Q9BQB6-1]
CCDS10704.1. [Q9BQB6-3]
RefSeqiNP_001298240.1. NM_001311311.1.
NP_076869.1. NM_024006.5. [Q9BQB6-1]
NP_996560.1. NM_206824.2. [Q9BQB6-3]
UniGeneiHs.324844.

3D structure databases

ProteinModelPortaliQ9BQB6.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi122472. 98 interactors.
IntActiQ9BQB6. 36 interactors.
STRINGi9606.ENSP00000378426.

Chemistry databases

BindingDBiQ9BQB6.
ChEMBLiCHEMBL1930.
DrugBankiDB01418. Acenocoumarol.
DB00266. Dicoumarol.
DB00170. Menadione.
DB00498. Phenindione.
DB00946. Phenprocoumon.
DB00682. Warfarin.
GuidetoPHARMACOLOGYi2645.

PTM databases

iPTMnetiQ9BQB6.
PhosphoSitePlusiQ9BQB6.
SwissPalmiQ9BQB6.

Polymorphism and mutation databases

BioMutaiVKORC1.
DMDMi62511226.

Proteomic databases

EPDiQ9BQB6.
MaxQBiQ9BQB6.
PaxDbiQ9BQB6.
PeptideAtlasiQ9BQB6.
PRIDEiQ9BQB6.

Protocols and materials databases

DNASUi79001.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000319788; ENSP00000326135; ENSG00000167397. [Q9BQB6-2]
ENST00000354895; ENSP00000346969; ENSG00000167397. [Q9BQB6-3]
ENST00000394975; ENSP00000378426; ENSG00000167397. [Q9BQB6-1]
GeneIDi79001.
KEGGihsa:79001.
UCSCiuc002eas.4. human. [Q9BQB6-1]

Organism-specific databases

CTDi79001.
DisGeNETi79001.
GeneCardsiVKORC1.
H-InvDBHIX0079837.
HGNCiHGNC:23663. VKORC1.
HPAiHPA042720.
MalaCardsiVKORC1.
MIMi122700. phenotype.
607473. phenotype.
608547. gene.
neXtProtiNX_Q9BQB6.
OpenTargetsiENSG00000167397.
Orphaneti98434. Hereditary combined deficiency of vitamin K-dependent clotting factors.
413684. Resistance to vitamin K antagonists.
413674. Vitamin K antagonists toxicity or dose selection.
PharmGKBiPA133787052.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410J0HT. Eukaryota.
ENOG4111UX7. LUCA.
GeneTreeiENSGT00390000002103.
HOGENOMiHOG000230752.
HOVERGENiHBG076672.
InParanoidiQ9BQB6.
KOiK05357.
OMAiWSSILLV.
OrthoDBiEOG091G0QTR.
PhylomeDBiQ9BQB6.
TreeFamiTF328467.

Enzyme and pathway databases

BioCyciZFISH:HS15548-MONOMER.
BRENDAi1.1.4.1. 2681.
ReactomeiR-HSA-6806664. Metabolism of vitamin K.

Miscellaneous databases

GeneWikiiVKORC1.
GenomeRNAii79001.
PROiQ9BQB6.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000167397.
CleanExiHS_VKORC1.
ExpressionAtlasiQ9BQB6. baseline and differential.
GenevisibleiQ9BQB6. HS.

Family and domain databases

InterProiIPR012932. VKOR.
[Graphical view]
PfamiPF07884. VKOR. 1 hit.
[Graphical view]
SMARTiSM00756. VKc. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiVKOR1_HUMAN
AccessioniPrimary (citable) accession number: Q9BQB6
Secondary accession number(s): A6NIQ6
, B2R4Z6, Q6UX90, Q7Z2R4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 12, 2005
Last sequence update: June 1, 2001
Last modified: November 2, 2016
This is version 132 of the entry and version 1 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

Miscellaneous

The location of two cysteine active-site residues within a proposed transmembrane is consistent both with the known hydrophobic environment of the thiol redox site of the enzyme and with the lipophilicity of vitamin K and warfarin (coumadin).

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 16
    Human chromosome 16: 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. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.