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Protein

Methylenetetrahydrofolate reductase

Gene

MTHFR

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

Functioni

Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine.1 Publication

Catalytic activityi

5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate + NAD(P)H.1 Publication

Cofactori

FAD1 Publication

Activity regulationi

Allosterically regulated by S-adenosylmethionine.

Pathwayi: tetrahydrofolate interconversion

This protein is involved in the pathway tetrahydrofolate interconversion, which is part of One-carbon metabolism.
View all proteins of this organism that are known to be involved in the pathway tetrahydrofolate interconversion and in One-carbon metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei63Proton donor/acceptorBy similarity1
Binding sitei127FADBy similarity1
Binding sitei159SubstrateBy similarity1
Binding sitei197FADBy similarity1
Binding sitei210FADBy similarity1
Binding sitei217FADBy similarity1
Binding sitei228SubstrateBy similarity1
Binding sitei321SubstrateBy similarity1
Binding sitei325SubstrateBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi63 – 68NADBy similarity6
Nucleotide bindingi94 – 95NAD and FADBy similarity2
Nucleotide bindingi157 – 159FADBy similarity3
Nucleotide bindingi174 – 175FADBy similarity2
Nucleotide bindingi201 – 204FADBy similarity4

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionAllosteric enzyme, Oxidoreductase
LigandFAD, Flavoprotein, NADP

Enzyme and pathway databases

BRENDAi1.5.1.20 2681
ReactomeiR-HSA-196757 Metabolism of folate and pterines
SABIO-RKiP42898
SIGNORiP42898
UniPathwayi
UPA00193

Names & Taxonomyi

Protein namesi
Recommended name:
Methylenetetrahydrofolate reductaseCurated (EC:1.5.1.201 Publication)
Gene namesi
Name:MTHFR
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000177000.10
HGNCiHGNC:7436 MTHFR
MIMi607093 gene
neXtProtiNX_P42898

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Pathology & Biotechi

Involvement in diseasei

Methylenetetrahydrofolate reductase deficiency (MTHFRD)7 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAutosomal recessive disorder with a wide range of features including homocysteinuria, homocysteinemia [MIM:603174], developmental delay, severe mental retardation, perinatal death, psychiatric disturbances, and later-onset neurodegenerative disorders.
See also OMIM:236250
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07411146R → Q in MTHFRD; reduces methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs776483190EnsemblClinVar.1
Natural variantiVAR_07411246R → W in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs138189536EnsemblClinVar.1
Natural variantiVAR_00953051R → P in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs201618781Ensembl.1
Natural variantiVAR_00431952R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant dbSNP:rs754980119Ensembl.1
Natural variantiVAR_07411359W → S in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs786204007EnsemblClinVar.1
Natural variantiVAR_07411468R → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs763539350EnsemblClinVar.1
Natural variantiVAR_07411582R → W in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204009EnsemblClinVar.1
Natural variantiVAR_074116113A → T in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs147257424EnsemblClinVar.1
Natural variantiVAR_074117127H → Y in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs769381688EnsemblClinVar.1
Natural variantiVAR_074118129T → N in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_074119130C → R in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204012EnsemblClinVar.1
Natural variantiVAR_074120147Q → P in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs786204013EnsemblClinVar.1
Natural variantiVAR_074121149G → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 Publication1
Natural variantiVAR_074122153I → M in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs767890671Ensembl.1
Natural variantiVAR_004320157R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant dbSNP:rs121434295EnsemblClinVar.1
Natural variantiVAR_074123175A → T in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs1182635980Ensembl.1
Natural variantiVAR_074124183R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs574132670EnsemblClinVar.1
Natural variantiVAR_074125195A → V in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs760161369Ensembl.1
Natural variantiVAR_074126196G → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204014EnsemblClinVar.1
Natural variantiVAR_074127215Missing in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 Publication1
Natural variantiVAR_074128218V → L in MTHFRD; decreased affinity for FAD cofactor. 1 Publication1
Natural variantiVAR_074129225I → L in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs200100285EnsemblClinVar.1
Natural variantiVAR_074130226Missing in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_004321227T → M in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs748571395Ensembl.1
Natural variantiVAR_004322251P → L in MTHFRD. 1 Publication1
Natural variantiVAR_074131253V → F in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_074132254P → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204017EnsemblClinVar.1
Natural variantiVAR_074133255G → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs786204018EnsemblClinVar.1
Natural variantiVAR_074134256I → N in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs373398993EnsemblClinVar.1
Natural variantiVAR_074135257F → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs786204019EnsemblClinVar.1
Natural variantiVAR_009531323L → P in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs121434297EnsemblClinVar.1
Natural variantiVAR_009532324N → S in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs267606887EnsemblClinVar.1
Natural variantiVAR_004323325R → C in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs371085894Ensembl.1
Natural variantiVAR_004324335R → C in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs748289202Ensembl.1
Natural variantiVAR_074136335R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs543016186EnsemblClinVar.1
Natural variantiVAR_074137338M → T in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs368321176Ensembl.1
Natural variantiVAR_009533339W → G in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 2 PublicationsCorresponds to variant dbSNP:rs267606886EnsemblClinVar.1
Natural variantiVAR_074138348P → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204021EnsemblClinVar.1
Natural variantiVAR_074139354H → Y in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204022EnsemblClinVar.1
Natural variantiVAR_004325357R → C in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs779993607Ensembl.1
Natural variantiVAR_074140363R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204023EnsemblClinVar.1
Natural variantiVAR_074141372K → E in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204024EnsemblClinVar.1
Natural variantiVAR_009534377R → C in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant dbSNP:rs121434296EnsemblClinVar.1
Natural variantiVAR_074142377R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs750323424Ensembl.1
Natural variantiVAR_009535387G → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant dbSNP:rs1430872491Ensembl.1
Natural variantiVAR_074143421W → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs200137991EnsemblClinVar.1
Natural variantiVAR_074144435F → S in MTHFRD. 2 PublicationsCorresponds to variant dbSNP:rs754015864Ensembl.1
Natural variantiVAR_074145506Y → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204026EnsemblClinVar.1
Natural variantiVAR_074146536V → F in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204028EnsemblClinVar.1
Natural variantiVAR_009536572P → L in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant dbSNP:rs144508139Ensembl.1
Natural variantiVAR_074147574V → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 Publications1
Natural variantiVAR_074148575V → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204031EnsemblClinVar.1
Natural variantiVAR_009537586E → K in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs983672500Ensembl.1
Natural variantiVAR_074149598L → P in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204034EnsemblClinVar.1
Natural variantiVAR_074150628L → P in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204037EnsemblClinVar.1
Ischemic stroke (ISCHSTR)1 Publication
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.
See also OMIM:601367
Neural tube defects, folate-sensitive (NTDFS)3 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionThe most common NTDs are open spina bifida (myelomeningocele) and anencephaly.
See also OMIM:601634
Schizophrenia (SCZD)2 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder.
See also OMIM:181500

Keywords - Diseasei

Disease mutation, Schizophrenia

Organism-specific databases

DisGeNETi4524
MalaCardsiMTHFR
MIMi181500 phenotype
236250 phenotype
601367 phenotype
601634 phenotype
603174 phenotype
OpenTargetsiENSG00000177000
Orphaneti268392 Cervical spina bifida aperta
268762 Cervical spina bifida cystica
268397 Cervicothoracic spina bifida aperta
268766 Cervicothoracic spina bifida cystica
395 Homocystinuria due to methylene tetrahydrofolate reductase deficiency
1048 Isolated anencephaly/exencephaly
268388 Lumbosacral spina bifida aperta
268758 Lumbosacral spina bifida cystica
413690 Methotrexate toxicity or dose selection
64738 Non rare thrombophilia
268384 Thoracolumbosacral spina bifida aperta
268752 Thoracolumbosacral spina bifida cystica
268377 Total spina bifida aperta
268748 Total spina bifida cystica
268740 Upper thoracic spina bifida aperta
268770 Upper thoracic spina bifida cystica
PharmGKBiPA245

Chemistry databases

DrugBankiDB00542 Benazepril
DB00115 Cyanocobalamin
DB00544 Fluorouracil
DB00158 Folic Acid
DB00134 L-Methionine
DB00170 Menadione
DB00563 Methotrexate
DB00140 Riboflavin
DB00116 Tetrahydrofolic acid

Polymorphism and mutation databases

BioMutaiMTHFR
DMDMi56405339

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001902451 – 656Methylenetetrahydrofolate reductaseAdd BLAST656

Proteomic databases

EPDiP42898
MaxQBiP42898
PaxDbiP42898
PeptideAtlasiP42898
PRIDEiP42898
ProteomicsDBi55566

PTM databases

iPTMnetiP42898
PhosphoSitePlusiP42898

Expressioni

Gene expression databases

BgeeiENSG00000177000 Expressed in 206 organ(s), highest expression level in corpus epididymis
CleanExiHS_MTHFR
ExpressionAtlasiP42898 baseline and differential
GenevisibleiP42898 HS

Organism-specific databases

HPAiHPA063389

Interactioni

Subunit structurei

Homodimer.

Protein-protein interaction databases

BioGridi110624, 26 interactors
IntActiP42898, 2 interactors
MINTiP42898
STRINGi9606.ENSP00000365775

Structurei

Secondary structure

1656
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP42898
SMRiP42898
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0564 Eukaryota
COG0685 LUCA
GeneTreeiENSGT00390000012490
HOGENOMiHOG000246234
HOVERGENiHBG006414
InParanoidiP42898
KOiK00297
OMAiMESGDKW
OrthoDBiEOG091G0YQK
PhylomeDBiP42898
TreeFamiTF105665

Family and domain databases

CDDicd00537 MTHFR, 1 hit
InterProiView protein in InterPro
IPR029041 FAD-linked_oxidoreductase-like
IPR004621 Fadh2_euk
IPR003171 Mehydrof_redctse
PfamiView protein in Pfam
PF02219 MTHFR, 1 hit
SUPFAMiSSF51730 SSF51730, 1 hit
TIGRFAMsiTIGR00677 fadh2_euk, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 8 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: P42898-1) [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
MVNEARGNSS LNPCLEGSAS SGSESSKDSS RCSTPGLDPE RHERLREKMR
60 70 80 90 100
RRLESGDKWF SLEFFPPRTA EGAVNLISRF DRMAAGGPLY IDVTWHPAGD
110 120 130 140 150
PGSDKETSSM MIASTAVNYC GLETILHMTC CRQRLEEITG HLHKAKQLGL
160 170 180 190 200
KNIMALRGDP IGDQWEEEEG GFNYAVDLVK HIRSEFGDYF DICVAGYPKG
210 220 230 240 250
HPEAGSFEAD LKHLKEKVSA GADFIITQLF FEADTFFRFV KACTDMGITC
260 270 280 290 300
PIVPGIFPIQ GYHSLRQLVK LSKLEVPQEI KDVIEPIKDN DAAIRNYGIE
310 320 330 340 350
LAVSLCQELL ASGLVPGLHF YTLNREMATT EVLKRLGMWT EDPRRPLPWA
360 370 380 390 400
LSAHPKRREE DVRPIFWASR PKSYIYRTQE WDEFPNGRWG NSSSPAFGEL
410 420 430 440 450
KDYYLFYLKS KSPKEELLKM WGEELTSEES VFEVFVLYLS GEPNRNGHKV
460 470 480 490 500
TCLPWNDEPL AAETSLLKEE LLRVNRQGIL TINSQPNING KPSSDPIVGW
510 520 530 540 550
GPSGGYVFQK AYLEFFTSRE TAEALLQVLK KYELRVNYHL VNVKGENITN
560 570 580 590 600
APELQPNAVT WGIFPGREII QPTVVDPVSF MFWKDEAFAL WIERWGKLYE
610 620 630 640 650
EESPSRTIIQ YIHDNYFLVN LVDNDFPLDN CLWQVVEDTL ELLNRPTQNA

RETEAP
Length:656
Mass (Da):74,597
Last modified:December 7, 2004 - v3
Checksum:iF16E774833D054B8
GO
Isoform 2 (identifier: P42898-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MDHRKARVLPAGHYCPSLGIWASQVGSVRSSVPPSISRNPAM

Show »
Length:697
Mass (Da):78,965
Checksum:i53BD7151AA16F795
GO

Computationally mapped potential isoform sequencesi

There are 8 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
L7P8G6L7P8G6_HUMAN
Methylenetetrahydrofolate reductase
MTHFR
411Annotation score:
A0A286YFD0A0A286YFD0_HUMAN
Methylenetetrahydrofolate reductase
MTHFR
642Annotation score:
A0A286YF17A0A286YF17_HUMAN
Methylenetetrahydrofolate reductase
MTHFR
549Annotation score:
Q5SNW5Q5SNW5_HUMAN
Methylenetetrahydrofolate reductase
MTHFR
143Annotation score:
Q5SNW7Q5SNW7_HUMAN
Methylenetetrahydrofolate reductase
MTHFR
155Annotation score:
F8W9T8F8W9T8_HUMAN
Methylenetetrahydrofolate reductase
MTHFR
229Annotation score:
A0A286YF47A0A286YF47_HUMAN
Methylenetetrahydrofolate reductase
MTHFR
82Annotation score:
A0A1B0GXD9A0A1B0GXD9_HUMAN
Methylenetetrahydrofolate reductase
MTHFR
29Annotation score:

Polymorphismi

Genetic variation in MTHFR influences susceptibility to occlusive vascular disease, neural tube defects (NTD), colon cancer and acute leukemia.

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07411146R → Q in MTHFRD; reduces methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs776483190EnsemblClinVar.1
Natural variantiVAR_07411246R → W in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs138189536EnsemblClinVar.1
Natural variantiVAR_00953051R → P in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs201618781Ensembl.1
Natural variantiVAR_00431952R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant dbSNP:rs754980119Ensembl.1
Natural variantiVAR_07411359W → S in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs786204007EnsemblClinVar.1
Natural variantiVAR_07411468R → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs763539350EnsemblClinVar.1
Natural variantiVAR_01488168R → Q1 PublicationCorresponds to variant dbSNP:rs2066472Ensembl.1
Natural variantiVAR_07411582R → W in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204009EnsemblClinVar.1
Natural variantiVAR_074116113A → T in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs147257424EnsemblClinVar.1
Natural variantiVAR_074117127H → Y in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs769381688EnsemblClinVar.1
Natural variantiVAR_074118129T → N in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_074119130C → R in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204012EnsemblClinVar.1
Natural variantiVAR_074120147Q → P in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs786204013EnsemblClinVar.1
Natural variantiVAR_074121149G → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 Publication1
Natural variantiVAR_074122153I → M in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs767890671Ensembl.1
Natural variantiVAR_004320157R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant dbSNP:rs121434295EnsemblClinVar.1
Natural variantiVAR_074123175A → T in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs1182635980Ensembl.1
Natural variantiVAR_074124183R → Q in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs574132670EnsemblClinVar.1
Natural variantiVAR_074125195A → V in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs760161369Ensembl.1
Natural variantiVAR_074126196G → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204014EnsemblClinVar.1
Natural variantiVAR_074127215Missing in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 Publication1
Natural variantiVAR_074128218V → L in MTHFRD; decreased affinity for FAD cofactor. 1 Publication1
Natural variantiVAR_009528222A → V Common polymorphism; at homozygosity reduces the risk for colorectal cancer in individuals with adequate folate status; decreased risk for adult acute leukemia; increased risk for NTDFS; increased risk for schizophrenia; thermolabile; decreased affinity for FAD cofactor; 50% reduced activity. 8 PublicationsCorresponds to variant dbSNP:rs1801133EnsemblClinVar.1
Natural variantiVAR_074129225I → L in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs200100285EnsemblClinVar.1
Natural variantiVAR_074130226Missing in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_004321227T → M in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs748571395Ensembl.1
Natural variantiVAR_004322251P → L in MTHFRD. 1 Publication1
Natural variantiVAR_074131253V → F in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 Publication1
Natural variantiVAR_074132254P → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204017EnsemblClinVar.1
Natural variantiVAR_074133255G → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs786204018EnsemblClinVar.1
Natural variantiVAR_074134256I → N in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs373398993EnsemblClinVar.1
Natural variantiVAR_074135257F → V in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs786204019EnsemblClinVar.1
Natural variantiVAR_009531323L → P in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs121434297EnsemblClinVar.1
Natural variantiVAR_009532324N → S in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs267606887EnsemblClinVar.1
Natural variantiVAR_004323325R → C in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs371085894Ensembl.1
Natural variantiVAR_004324335R → C in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs748289202Ensembl.1
Natural variantiVAR_074136335R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs543016186EnsemblClinVar.1
Natural variantiVAR_074137338M → T in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 1 PublicationCorresponds to variant dbSNP:rs368321176Ensembl.1
Natural variantiVAR_009533339W → G in MTHFRD; loss of methylenetetrahydrofolate reductase activity. 2 PublicationsCorresponds to variant dbSNP:rs267606886EnsemblClinVar.1
Natural variantiVAR_074138348P → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204021EnsemblClinVar.1
Natural variantiVAR_074139354H → Y in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204022EnsemblClinVar.1
Natural variantiVAR_004325357R → C in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs779993607Ensembl.1
Natural variantiVAR_074140363R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204023EnsemblClinVar.1
Natural variantiVAR_074141372K → E in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204024EnsemblClinVar.1
Natural variantiVAR_009534377R → C in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant dbSNP:rs121434296EnsemblClinVar.1
Natural variantiVAR_074142377R → H in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs750323424Ensembl.1
Natural variantiVAR_009535387G → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant dbSNP:rs1430872491Ensembl.1
Natural variantiVAR_074143421W → S in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs200137991EnsemblClinVar.1
Natural variantiVAR_018857422G → R1 PublicationCorresponds to variant dbSNP:rs45571736Ensembl.1
Natural variantiVAR_014882429E → A Common polymorphism; decreased risk for adult acute leukemia; thermolabile; decreased activity. 4 PublicationsCorresponds to variant dbSNP:rs1801131EnsemblClinVar.1
Natural variantiVAR_074144435F → S in MTHFRD. 2 PublicationsCorresponds to variant dbSNP:rs754015864Ensembl.1
Natural variantiVAR_054158470E → A1 Publication1
Natural variantiVAR_074145506Y → D in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204026EnsemblClinVar.1
Natural variantiVAR_018858519R → C1 PublicationCorresponds to variant dbSNP:rs45496998Ensembl.1
Natural variantiVAR_050293519R → H. Corresponds to variant dbSNP:rs45449298Ensembl.1
Natural variantiVAR_074146536V → F in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204028EnsemblClinVar.1
Natural variantiVAR_050294566G → E. Corresponds to variant dbSNP:rs2274974Ensembl.1
Natural variantiVAR_009536572P → L in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 PublicationsCorresponds to variant dbSNP:rs144508139Ensembl.1
Natural variantiVAR_074147574V → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 2 Publications1
Natural variantiVAR_074148575V → G in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204031EnsemblClinVar.1
Natural variantiVAR_009537586E → K in MTHFRD. 1 PublicationCorresponds to variant dbSNP:rs983672500Ensembl.1
Natural variantiVAR_018859594R → Q2 PublicationsCorresponds to variant dbSNP:rs2274976EnsemblClinVar.1
Natural variantiVAR_074149598L → P in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204034EnsemblClinVar.1
Natural variantiVAR_074150628L → P in MTHFRD; reduced methylenetetrahydrofolate reductase activity; reduced affinity for NADPH. 1 PublicationCorresponds to variant dbSNP:rs786204037EnsemblClinVar.1
Natural variantiVAR_018860653T → M1 PublicationCorresponds to variant dbSNP:rs35737219EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0537441M → MDHRKARVLPAGHYCPSLGI WASQVGSVRSSVPPSISRNP AM in isoform 2. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U09806 mRNA Translation: AAA74440.2
AF105987
, AF105977, AF105978, AF105979, AF105980, AF105981, AF105982, AF105983, AF105984, AF105985, AF105986 Genomic DNA Translation: AAD17965.1
AJ237672 mRNA Translation: CAB41971.1
AK312907 mRNA Translation: BAG35753.1
AY338232 Genomic DNA Translation: AAP88033.1
AL953897 Genomic DNA No translation available.
CH471130 Genomic DNA Translation: EAW71709.1
BC053509 mRNA Translation: AAH53509.1
AY046562 mRNA Translation: AAL17648.1
AF398930 Genomic DNA Translation: AAN40865.1
CCDSiCCDS137.1 [P42898-1]
CCDS81262.1 [P42898-2]
PIRiS46454
RefSeqiNP_001317287.1, NM_001330358.1 [P42898-2]
NP_005948.3, NM_005957.4 [P42898-1]
XP_005263517.1, XM_005263460.4 [P42898-1]
XP_005263519.1, XM_005263462.4 [P42898-1]
UniGeneiHs.214142
Hs.737916

Genome annotation databases

EnsembliENST00000376583; ENSP00000365767; ENSG00000177000 [P42898-2]
ENST00000376585; ENSP00000365770; ENSG00000177000 [P42898-2]
ENST00000376590; ENSP00000365775; ENSG00000177000 [P42898-1]
ENST00000376592; ENSP00000365777; ENSG00000177000 [P42898-1]
GeneIDi4524
KEGGihsa:4524
UCSCiuc001atc.3 human [P42898-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology
NIEHS-SNPs
SHMPD

The Singapore human mutation and polymorphism database

Wikipedia

Methylenetetrahydrofolate reductase entry

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U09806 mRNA Translation: AAA74440.2
AF105987
, AF105977, AF105978, AF105979, AF105980, AF105981, AF105982, AF105983, AF105984, AF105985, AF105986 Genomic DNA Translation: AAD17965.1
AJ237672 mRNA Translation: CAB41971.1
AK312907 mRNA Translation: BAG35753.1
AY338232 Genomic DNA Translation: AAP88033.1
AL953897 Genomic DNA No translation available.
CH471130 Genomic DNA Translation: EAW71709.1
BC053509 mRNA Translation: AAH53509.1
AY046562 mRNA Translation: AAL17648.1
AF398930 Genomic DNA Translation: AAN40865.1
CCDSiCCDS137.1 [P42898-1]
CCDS81262.1 [P42898-2]
PIRiS46454
RefSeqiNP_001317287.1, NM_001330358.1 [P42898-2]
NP_005948.3, NM_005957.4 [P42898-1]
XP_005263517.1, XM_005263460.4 [P42898-1]
XP_005263519.1, XM_005263462.4 [P42898-1]
UniGeneiHs.214142
Hs.737916

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
6FCXX-ray2.50A/B37-644[»]
ProteinModelPortaliP42898
SMRiP42898
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi110624, 26 interactors
IntActiP42898, 2 interactors
MINTiP42898
STRINGi9606.ENSP00000365775

Chemistry databases

DrugBankiDB00542 Benazepril
DB00115 Cyanocobalamin
DB00544 Fluorouracil
DB00158 Folic Acid
DB00134 L-Methionine
DB00170 Menadione
DB00563 Methotrexate
DB00140 Riboflavin
DB00116 Tetrahydrofolic acid

PTM databases

iPTMnetiP42898
PhosphoSitePlusiP42898

Polymorphism and mutation databases

BioMutaiMTHFR
DMDMi56405339

Proteomic databases

EPDiP42898
MaxQBiP42898
PaxDbiP42898
PeptideAtlasiP42898
PRIDEiP42898
ProteomicsDBi55566

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000376583; ENSP00000365767; ENSG00000177000 [P42898-2]
ENST00000376585; ENSP00000365770; ENSG00000177000 [P42898-2]
ENST00000376590; ENSP00000365775; ENSG00000177000 [P42898-1]
ENST00000376592; ENSP00000365777; ENSG00000177000 [P42898-1]
GeneIDi4524
KEGGihsa:4524
UCSCiuc001atc.3 human [P42898-1]

Organism-specific databases

CTDi4524
DisGeNETi4524
EuPathDBiHostDB:ENSG00000177000.10
GeneCardsiMTHFR
HGNCiHGNC:7436 MTHFR
HPAiHPA063389
MalaCardsiMTHFR
MIMi181500 phenotype
236250 phenotype
601367 phenotype
601634 phenotype
603174 phenotype
607093 gene
neXtProtiNX_P42898
OpenTargetsiENSG00000177000
Orphaneti268392 Cervical spina bifida aperta
268762 Cervical spina bifida cystica
268397 Cervicothoracic spina bifida aperta
268766 Cervicothoracic spina bifida cystica
395 Homocystinuria due to methylene tetrahydrofolate reductase deficiency
1048 Isolated anencephaly/exencephaly
268388 Lumbosacral spina bifida aperta
268758 Lumbosacral spina bifida cystica
413690 Methotrexate toxicity or dose selection
64738 Non rare thrombophilia
268384 Thoracolumbosacral spina bifida aperta
268752 Thoracolumbosacral spina bifida cystica
268377 Total spina bifida aperta
268748 Total spina bifida cystica
268740 Upper thoracic spina bifida aperta
268770 Upper thoracic spina bifida cystica
PharmGKBiPA245
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0564 Eukaryota
COG0685 LUCA
GeneTreeiENSGT00390000012490
HOGENOMiHOG000246234
HOVERGENiHBG006414
InParanoidiP42898
KOiK00297
OMAiMESGDKW
OrthoDBiEOG091G0YQK
PhylomeDBiP42898
TreeFamiTF105665

Enzyme and pathway databases

UniPathwayi
UPA00193

BRENDAi1.5.1.20 2681
ReactomeiR-HSA-196757 Metabolism of folate and pterines
SABIO-RKiP42898
SIGNORiP42898

Miscellaneous databases

ChiTaRSiMTHFR human
GeneWikiiMethylenetetrahydrofolate_reductase
GenomeRNAii4524
PROiPR:P42898
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000177000 Expressed in 206 organ(s), highest expression level in corpus epididymis
CleanExiHS_MTHFR
ExpressionAtlasiP42898 baseline and differential
GenevisibleiP42898 HS

Family and domain databases

CDDicd00537 MTHFR, 1 hit
InterProiView protein in InterPro
IPR029041 FAD-linked_oxidoreductase-like
IPR004621 Fadh2_euk
IPR003171 Mehydrof_redctse
PfamiView protein in Pfam
PF02219 MTHFR, 1 hit
SUPFAMiSSF51730 SSF51730, 1 hit
TIGRFAMsiTIGR00677 fadh2_euk, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiMTHR_HUMAN
AccessioniPrimary (citable) accession number: P42898
Secondary accession number(s): B2R7A6
, Q5SNW6, Q5SNW9, Q7Z6M6, Q8IU73, Q9UQR2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: December 7, 2004
Last modified: October 10, 2018
This is version 182 of the entry and version 3 of the sequence. See 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

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: 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. SIMILARITY comments
    Index of protein domains and families
  4. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  7. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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