{"gene":{"symbol":"MTHFR","name":"5,10-Methylenetetrahydrofolate reductase","protein":"Methylenetetrahydrofolate reductase","ncbi_gene_id":"4524","locus":"1p36.22","summary":"MTHFR encodes the enzyme that converts dietary folate into its biologically active form, 5-methyltetrahydrofolate. Two common variants, C677T (rs1801133) and A1298C (rs1801131), reduce enzyme activity. Carrying either variant is common and, with adequate dietary folate, almost always clinically silent.","function":"The MTHFR enzyme sits at a central node in one-carbon metabolism: it converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which donates a methyl group to homocysteine to regenerate methionine. Methionine is then activated to S-adenosylmethionine (SAM), the universal methyl donor used by hundreds of methyltransferases for DNA methylation, neurotransmitter synthesis and phospholipid production. When MTHFR activity drops, homocysteine can accumulate in plasma and the supply of methylated folate to downstream reactions can be tight; both effects are blunted in people with adequate folate intake, which is why folate fortification of grain has substantially reduced the population-level impact of MTHFR variants. MTHFR is not a switch for health: it is one of dozens of enzymes that buffer the methylation cycle, and the system has substantial redundancy.","category":"nutrigenomics","key_variants":[{"rsid":"rs1801133","name":"C677T (Ala222Val, exon 4)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): G reference, A variant. MTHFR is on the minus strand, so A here is the T of c.665C>T, known as C677T.","effect":"Reduces enzyme thermostability. 677TT homozygotes have ~30% of normal enzyme activity; 677CT heterozygotes ~65% (lymphocyte extracts, Frosst et al., Nat Genet 1995).","frequency_note":"677T allele (A on the plus strand) frequency ~37% in Europeans, ~47% in Admixed Americans, ~9% in Africans (1000 Genomes, Ensembl)."},{"rsid":"rs1801131","name":"A1298C (Glu429Ala, exon 7)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): T reference, G variant. MTHFR is on the minus strand, so G here is the C of c.1286A>C, known as A1298C.","effect":"Smaller effect on enzyme activity than C677T: in one lymphocyte study, 1298CC homozygotes had about 60% of control activity, and compound heterozygotes (677CT/1298AC) 50–60%, lower than single 677CT heterozygotes (Weisberg et al., Mol Genet Metab 1998).","frequency_note":"1298C allele (G on the plus strand) frequency ~30% in Europeans."},{"rsid":"rs2274976","name":"G1793A (Arg594Gln, exon 11)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): C reference, T variant. MTHFR is on the minus strand, so T here is the A of c.1781G>A (Arg594Gln), known as G1793A.","effect":"Missense variant, uncommon in Africans and Europeans (~2–3%) and common in South and East Asians (~12–17%), with limited clinical evidence; ClinVar classifies it as benign (VCV000194071).","frequency_note":"T on the plus strand (the gene’s A) about 7% pooled in 1000 Genomes: ~2% African, ~3% European, ~4% Admixed American, ~12% East Asian, ~17% South Asian (Ensembl)."}],"phenotypes":["677CC: normal enzyme activity","677CT: ~65% of normal enzyme activity","677TT: ~30% of normal enzyme activity","677CT + 1298AC compound heterozygote: about 50–60% of control activity in one lymphocyte study, lower than 677CT alone (Weisberg et al., 1998)"],"clinical_relevance":"In ClinVar, C677T has the aggregate classification drug response (methotrexate toxicity; reviewed by an expert panel, VCV000003520), although a DPWG guideline found insufficient evidence for an MTHFR–methotrexate gene–drug interaction (van der Pol et al., Eur J Hum Genet 2024); A1298C has conflicting classifications (VCV000003521); neither is an established cause of disease on its own. The American College of Medical Genetics and Genomics has explicitly recommended against routine MTHFR testing for thrombophilia or recurrent pregnancy loss workups, because the absolute risk increase is small and folate supplementation acts independently of genotype. What the high-quality evidence supports: 677TT homozygotes have modestly elevated plasma homocysteine when folate intake is low, and the effect largely disappears with adequate folate; severe MTHFR deficiency (rare, distinct biallelic loss-of-function variants, not the common C677T/A1298C) causes homocystinuria, listed in ClinVar as Pathogenic; routine supplementation with methylfolate (5-MTHF) instead of folic acid is not required for C677T or A1298C carriers in the general population. Most carriers of even the homozygous 677TT genotype are clinically indistinguishable from non-carriers when folate intake is adequate. DeepDNA's MTHFR article limits clinical relevance to pregnancy planning (neural tube defect risk when maternal folate intake is low), methotrexate treatment, and persistently elevated homocysteine.","consumer_array_caveat":"rs1801133 (C677T) and rs1801131 (A1298C) can be located directly in raw genotype data from 23andMe, AncestryDNA, MyHeritage or a clinical VCF. 23andMe raw data reports the plus strand of GRCh37, where rs1801133 shows G or A: MTHFR is on the minus strand, so A there is the T of C677T. A file that shows C or T is reporting the gene’s strand.","drugs":[{"drug":"methotrexate","guideline":null,"level":"CPIC C (provisional)","summary":"Methotrexate is a folate antagonist, and MTHFR variants have been studied as a factor in its side effects. One cross-sectional study of 214 rheumatoid arthritis patients found 677TT associated with central-nervous-system side effects of methotrexate (Weisman et al., Arthritis Rheum 2006). A DPWG guideline found insufficient evidence for an MTHFR–methotrexate gene–drug interaction (van der Pol et al., Eur J Hum Genet 2024)."}],"sources":[{"label":"ClinVar — MTHFR gene entries","url":"https://www.ncbi.nlm.nih.gov/clinvar/?term=MTHFR%5Bgene%5D"},{"label":"OMIM 607093 — MTHFR","url":"https://www.omim.org/entry/607093"},{"label":"NCBI Gene 4524","url":"https://www.ncbi.nlm.nih.gov/gene/4524"},{"label":"Hickey et al., Genet Med 2013 (ACMG practice guideline: lack of evidence for MTHFR polymorphism testing)","url":"https://pubmed.ncbi.nlm.nih.gov/23288205/"},{"label":"Botto & Yang, Am J Epidemiol 2000 (HuGE review: MTHFR variants and congenital anomalies, incl. maternal 677TT and neural tube defects)","url":"https://pubmed.ncbi.nlm.nih.gov/10791559/"},{"label":"Frosst et al., Nat Genet 1995 (MTHFR C677T: reduced, thermolabile enzyme activity in lymphocyte extracts; higher plasma homocysteine in homozygotes)","url":"https://pubmed.ncbi.nlm.nih.gov/7647779/"},{"label":"Weisman et al., Arthritis Rheum 2006 (folate-pathway risk genotypes, incl. MTHFR 677TT, and methotrexate side effects in rheumatoid arthritis)","url":"https://pubmed.ncbi.nlm.nih.gov/16447238/"},{"label":"van der Pol et al., Eur J Hum Genet 2024 (DPWG guideline: ABCG2/HLA-B and allopurinol, MTHFR and folic acid/methotrexate)","url":"https://pubmed.ncbi.nlm.nih.gov/36056234/"},{"label":"Weisberg et al., Mol Genet Metab 1998 (MTHFR A1298C and decreased enzyme activity)","url":"https://pubmed.ncbi.nlm.nih.gov/9719624/"}],"related_blog":"/blog/mthfr-gene-explained/","disclaimer":"Educational information only, not medical advice or diagnosis. Consult a clinician before acting on genetic information."},"meta":{"disclaimer":"Educational information only, not medical advice or diagnosis. Consult a clinician before acting on genetic information.","api_version":"2026-09-20","docs":"https://deepdna.ai/docs/","status":"live","data_as_of":"2026-10-25T21:32:19.251Z","freshness":"https://deepdna.ai/api/v1/freshness"}}