U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Links from MedGen

    • Showing Current items.

    MTHFR methylenetetrahydrofolate reductase [ Homo sapiens (human) ]

    Gene ID: 4524, updated on 3-Apr-2024

    Summary

    Go to the top of the page Help
    Official Symbol
    MTHFRprovided by HGNC
    Official Full Name
    methylenetetrahydrofolate reductaseprovided by HGNC
    Primary source
    HGNC:HGNC:7436
    See related
    Ensembl:ENSG00000177000 MIM:607093; AllianceGenome:HGNC:7436
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Summary
    The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]
    Expression
    Ubiquitous expression in lung (RPKM 7.5), thyroid (RPKM 7.2) and 25 other tissues See more
    Orthologs
    mouse all
    NEW
    Try the new Gene table
    Try the new Transcript table

    Genomic context

    Go to the top of the page Help
    Location:
    1p36.22
    Exon count:
    13
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 1 NC_000001.11 (11785723..11805964, complement)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 1 NC_060925.1 (11329802..11350048, complement)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 1 NC_000001.10 (11845780..11866021, complement)

    Chromosome 1 - NC_000001.11Genomic Context describing neighboring genes Neighboring gene atrophin-1-like Neighboring gene chromosome 1 open reading frame 167 Neighboring gene C1orf167 antisense RNA 1 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr1:11847781-11848588 Neighboring gene ReSE screen-validated silencer GRCh37_chr1:11851353-11851865 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr1:11860626-11861224 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr1:11862804-11863700 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr1:11863701-11864596 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 272 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 273 Neighboring gene H3K27ac hESC enhancer GRCh37_chr1:11865893-11866878 Neighboring gene chloride voltage-gated channel 6 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 178 Neighboring gene NPPA antisense RNA 1 Neighboring gene VISTA enhancer hs2123 Neighboring gene natriuretic peptide A

    Genomic regions, transcripts, and products

    Go to the top of the page Help

    Go to nucleotide: Graphics FASTA GenBank

    Expression

    Go to the top of the page Help
    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

    Go to the top of the pageHelp

    Related articles in PubMed

    1. Effects of folic acid supplementation on chronic atrophic gastritis based on MTHFR C677T polymorphism. Kong S, et al. Medicine (Baltimore), 2023 Jun 16. PMID 37327296, Free PMC Article
    2. Plasma thiol levels and methylenetetrahydrofolate reductase gene c.665C > T and c.1286A > C variants affect fibrin clot properties in Polish venous thromboembolic patients. Klajmon A, et al. Mol Genet Metab, 2023 Jul. PMID 37302269
    3. Dual effect of methylene-tetrahydrofolate reductase and angiotensinconverting enzyme gene polymorphisms on the risk of acute ischemic stroke. Karakus N, et al. J Genet, 2023. PMID 37204128
    4. Maternal pre-pregnancy BMI, MTHFR polymorphisms, and the risk of adverse pregnancy outcomes in pregnant women from South China: a retrospective cohort study. Gu C, et al. BMC Pregnancy Childbirth, 2023 Apr 27. PMID 37106323, Free PMC Article
    5. Methylenetetrahydrofolate reductase polymorphisms and elevated plasma homocysteine levels in small vessel disease. Chen L, et al. Brain Behav, 2023 May. PMID 36978223, Free PMC Article

    See all (3805) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. [Analysis of 9 patients with adolescence-onset methylenetetrahydrofolate reductase deficiency].
      Title: [Analysis of 9 patients with adolescence-onset methylenetetrahydrofolate reductase deficiency].
    2. Interaction effects of MTHFR C677T and A1298C polymorphisms with maternal glycated haemoglobin levels on adverse birth outcomes.
      Title: Interaction effects of MTHFR C677T and A1298C polymorphisms with maternal glycated haemoglobin levels on adverse birth outcomes.
    3. Association between MTHFR C677T Gene Polymorphisms and the Efficacy of Vitamin Therapy in lowering Homocysteine Levels among Stroke Patients with Hyperhomocysteinemia.
      Title: Association between MTHFR C677T Gene Polymorphisms and the Efficacy of Vitamin Therapy in lowering Homocysteine Levels among Stroke Patients with Hyperhomocysteinemia.
    4. Association between maternal diet, smoking, and the placenta MTHFR 677C/T genotype and global placental DNA methylation.
      Title: Association between maternal diet, smoking, and the placenta MTHFR 677C/T genotype and global placental DNA methylation.
    5. Congenital septal defects in Karachi, Pakistan: an update of mutational screening by high-resolution melting (HRM) analysis of MTHFR C677T.
      Title: Congenital septal defects in Karachi, Pakistan: an update of mutational screening by high-resolution melting (HRM) analysis of MTHFR C677T.
    6. Relationship between methylenetetrahydrofolate reductase C677T gene polymorphism and neutrophil gelatinase-associated lipocalin in early renal injury in H-type hypertension.
      Title: Relationship between methylenetetrahydrofolate reductase C677T gene polymorphism and neutrophil gelatinase-associated lipocalin in early renal injury in H-type hypertension.
    7. Association of methylenetetrahydrofolate reductase gene variant C677T and folate levels in non-syndromic cleft lip/palate among Sindhi, Pakistani population.
      Title: Association of methylenetetrahydrofolate reductase gene variant C677T and folate levels in non-syndromic cleft lip/palate among Sindhi, Pakistani population.
    8. A Comprehensive Investigation into the Association Between Mthfr C677t, A1298c, and Ace I/D Variants and Risk of Migraine: an Updated Meta-Analysis of Genetic Association Studies with Trial Sequential Analysis and Meta-Regression.
      Title: A Comprehensive Investigation into the Association Between Mthfr C677t, A1298c, and Ace I/D Variants and Risk of Migraine: an Updated Meta-Analysis of Genetic Association Studies with Trial Sequential Analysis and Meta-Regression.
    9. Association study between genetic polymorphisms in MTHFR and stroke susceptibility in Egyptian population: a case-control study.
      Title: Association study between genetic polymorphisms in MTHFR and stroke susceptibility in Egyptian population: a case-control study.
    10. MTHFR and risk of stroke and heart disease in a low-folate population: a prospective study of 156 000 Chinese adults.
      Title: MTHFR and risk of stroke and heart disease in a low-folate population: a prospective study of 156 000 Chinese adults.
    Submit: New GeneRIF Correction See all GeneRIFs (2582)

    Phenotypes

    Go to the top of the page Help

    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Homocystinuria due to methylene tetrahydrofolate reductase deficiency
    MedGen: C1856058 OMIM: 236250 GeneReviews: Not available
    		Compare labs
    Neural tube defects, folate-sensitive
    MedGen: C1866558 OMIM: 601634 GeneReviews: Not available
    		Compare labs
    Schizophrenia
    MedGen: C0036341 OMIM: 181500 GeneReviews: Not available
    		Compare labs
    Thrombophilia due to thrombin defect
    MedGen: C3160733 OMIM: 188050 GeneReviews: Prothrombin Thrombophilia
    		Compare labs

    EBI GWAS Catalog

    Description
    Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease.
    EBI GWAS Catalog
    Genome-wide association study identifies eight loci associated with blood pressure.
    EBI GWAS Catalog
    Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.
    EBI GWAS Catalog
    Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway.
    EBI GWAS Catalog
    Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine in a healthy population: a genome-wide evaluation of 13 974 participants in the Women's Genome Health Study.
    EBI GWAS Catalog
    Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.
    EBI GWAS Catalog

    Variation

    Go to the top of the page Help

    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    Pathways from PubChem

    Go to the top of the page

    Interactions

    Go to the top of the page Help
    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

    Go to the top of the page Help

    Markers

    Homology

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables FAD binding IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables NADP binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables flavin adenine dinucleotide binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables methylenetetrahydrofolate reductase (NAD(P)H) activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables methylenetetrahydrofolate reductase (NAD(P)H) activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables methylenetetrahydrofolate reductase (NAD(P)H) activity IGI
    Inferred from Genetic Interaction
    more info
    		 PubMed 
    enables methylenetetrahydrofolate reductase (NAD(P)H) activity IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    enables methylenetetrahydrofolate reductase NADPH activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables modified amino acid binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables protein-containing complex binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in S-adenosylmethionine metabolic process IEA
    Inferred from Electronic Annotation
    more info
    		  
    acts_upstream_of heterochromatin organization IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in homocysteine metabolic process IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in methionine biosynthetic process IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in methionine metabolic process IGI
    Inferred from Genetic Interaction
    more info
    		 PubMed 
    acts_upstream_of neural tube closure IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    acts_upstream_of neural tube closure NAS
    Non-traceable Author Statement
    more info
    		 PubMed 
    involved_in response to amino acid IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in response to folic acid IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in response to hypoxia IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in response to interleukin-1 IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in response to vitamin B2 IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in response to xenobiotic stimulus IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in tetrahydrofolate interconversion IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in tetrahydrofolate interconversion IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in tetrahydrofolate interconversion IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in tetrahydrofolate interconversion IGI
    Inferred from Genetic Interaction
    more info
    		 PubMed 
    involved_in tetrahydrofolate interconversion IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    Component Evidence Code Pubs
    located_in cytosol TAS
    Traceable Author Statement
    more info
    		  

    General protein information

    Go to the top of the page Help
    Preferred Names
    methylenetetrahydrofolate reductase (NADPH)
    Names
    5,10-methylenetetrahydrofolate reductase (NADPH)
    methylenetetrahydrofolate reductase (NAD(P)H)
    NP_001317287.1
    NP_001397679.1
    NP_005948.3
    XP_005263519.1
    XP_005263520.1
    XP_011539798.1
    XP_016856817.1
    XP_047277130.1
    XP_047277134.1
    XP_047277135.1
    XP_047277136.1
    XP_047277137.1
    XP_054192675.1
    XP_054192676.1
    XP_054192677.1
    XP_054192678.1
    XP_054192679.1
    XP_054192680.1
    XP_054192681.1
    XP_054192682.1

    NCBI Reference Sequences (RefSeq)

    Go to the top of the page Help

    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_013351.1 RefSeqGene

      Range
      5001..25374
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_726

    mRNA and Protein(s)

    1. NM_001330358.2 → NP_001317287.1  methylenetetrahydrofolate reductase (NADPH) isoform 1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longer isoform (1).
      Source sequence(s)
      AL953897
      Consensus CDS
      CCDS81262.1
      UniProtKB/TrEMBL
      Q59GJ6
      Related
      ENSP00000365767.3, ENST00000376583.7

    2. NM_001410750.1 → NP_001397679.1  methylenetetrahydrofolate reductase (NADPH) isoform 3

      Status: REVIEWED

      Source sequence(s)
      AL953897
      Consensus CDS
      CCDS90864.1
      UniProtKB/TrEMBL
      Q5SNW7
      Related
      ENSP00000398908.3, ENST00000423400.7

    3. NM_005957.5 → NP_005948.3  methylenetetrahydrofolate reductase (NADPH) isoform 2

      See identical proteins and their annotated locations for NP_005948.3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) differs in the 5' UTR and coding sequence compared to variant 1. The resulting isoform (2) is shorter at the N-terminus compared to isoform 1.
      Source sequence(s)
      AB209113, AJ237672, AL953897, AY046560, BC053509
      Consensus CDS
      CCDS137.1
      UniProtKB/Swiss-Prot
      B2R7A6, P42898, Q5SNW6, Q5SNW9, Q7Z6M6, Q8IU73, Q9UQR2
      UniProtKB/TrEMBL
      A0A286YF17
      Related
      ENSP00000365775.3, ENST00000376590.9
      Conserved Domains (1) summary
      cl00246
      Location:60 → 626
      MTHFR; Methylenetetrahydrofolate reductase (MTHFR). 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase, a cytoplasmic, NAD(P)-dependent enzyme. 5-methyltetrahydrofolate is utilized by methionine synthase ...

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000001.11 Reference GRCh38.p14 Primary Assembly

      Range
      11785723..11805964 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047421181.1 → XP_047277137.1  methylenetetrahydrofolate reductase (NADPH) isoform X6

    2. XM_005263462.5 → XP_005263519.1  methylenetetrahydrofolate reductase (NADPH) isoform X3

      See identical proteins and their annotated locations for XP_005263519.1

      UniProtKB/Swiss-Prot
      B2R7A6, P42898, Q5SNW6, Q5SNW9, Q7Z6M6, Q8IU73, Q9UQR2
      UniProtKB/TrEMBL
      A0A286YF17
      Conserved Domains (1) summary
      cl00246
      Location:60 → 626
      MTHFR; Methylenetetrahydrofolate reductase (MTHFR). 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase, a cytoplasmic, NAD(P)-dependent enzyme. 5-methyltetrahydrofolate is utilized by methionine synthase ...

    3. XM_047421179.1 → XP_047277135.1  methylenetetrahydrofolate reductase (NADPH) isoform X5

      UniProtKB/TrEMBL
      A0A286YFD0
      Related
      ENSP00000493098.1, ENST00000641407.1

    4. XM_047421180.1 → XP_047277136.1  methylenetetrahydrofolate reductase (NADPH) isoform X6

      Related
      ENSP00000493262.1, ENST00000641446.1

    5. XM_047421178.1 → XP_047277134.1  methylenetetrahydrofolate reductase (NADPH) isoform X3

      UniProtKB/Swiss-Prot
      B2R7A6, P42898, Q5SNW6, Q5SNW9, Q7Z6M6, Q8IU73, Q9UQR2
      Related
      ENSP00000365777.1, ENST00000376592.6

    6. XM_047421174.1 → XP_047277130.1  methylenetetrahydrofolate reductase (NADPH) isoform X2

    7. XM_011541496.4 → XP_011539798.1  methylenetetrahydrofolate reductase (NADPH) isoform X1

      UniProtKB/TrEMBL
      Q59GJ6
      Conserved Domains (1) summary
      cl00246
      Location:101 → 625
      MTHFR; Methylenetetrahydrofolate reductase (MTHFR). 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase, a cytoplasmic, NAD(P)-dependent enzyme. 5-methyltetrahydrofolate is utilized by methionine synthase ...

    8. XM_017001328.3 → XP_016856817.1  methylenetetrahydrofolate reductase (NADPH) isoform X4

      UniProtKB/TrEMBL
      A0A286YF17

    9. XM_005263463.5 → XP_005263520.1  methylenetetrahydrofolate reductase (NADPH) isoform X7

      UniProtKB/TrEMBL
      A0A286YF17
      Conserved Domains (1) summary
      cl00246
      Location:1 → 544
      MTHFR; Methylenetetrahydrofolate reductase (MTHFR). 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase, a cytoplasmic, NAD(P)-dependent enzyme. 5-methyltetrahydrofolate is utilized by methionine synthase ...

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060925.1 Alternate T2T-CHM13v2.0

      Range
      11329802..11350048 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054336702.1 → XP_054192677.1  methylenetetrahydrofolate reductase (NADPH) isoform X3

    2. XM_054336707.1 → XP_054192682.1  methylenetetrahydrofolate reductase (NADPH) isoform X7

    3. XM_054336706.1 → XP_054192681.1  methylenetetrahydrofolate reductase (NADPH) isoform X6

    4. XM_054336704.1 → XP_054192679.1  methylenetetrahydrofolate reductase (NADPH) isoform X5

    5. XM_054336705.1 → XP_054192680.1  methylenetetrahydrofolate reductase (NADPH) isoform X6

    6. XM_054336701.1 → XP_054192676.1  methylenetetrahydrofolate reductase (NADPH) isoform X2

    7. XM_054336700.1 → XP_054192675.1  methylenetetrahydrofolate reductase (NADPH) isoform X1

    8. XM_054336703.1 → XP_054192678.1  methylenetetrahydrofolate reductase (NADPH) isoform X4

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    P42898.3 GenPept UniProtKB/Swiss-Prot:P42898

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

    Chemical Information
    Medical
    Molecular Biology Databases
    Research Materials
    Tools
    Miscellaneous