MTHFR
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. The clinical impact of carrying these variants is far smaller than the wellness internet suggests.
The methylation hub.
The MTHFR enzyme sits at a central node in one-carbon metabolism. Its job is to convert 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, two things can happen: 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. This is why folate fortification of grain (mandatory in the US and many other countries since the late 1990s) 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. Most carriers of even the homozygous 677TT genotype are clinically indistinguishable from non-carriers when folate intake is adequate.
Two SNPs do most of the talking.
What the evidence actually says.
ClinVar — the NIH's curated database of variant–disease associations — gives C677T 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 does support:
- 677TT homozygotes have modestly elevated plasma homocysteine when folate intake is low. The effect largely disappears with adequate folate.
- Severe MTHFR deficiency (rare, distinct biallelic loss-of-function variants — not the common C677T/A1298C) causes homocystinuria, a clinically significant inborn error of metabolism 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.
"Carrying MTHFR C677T or A1298C is common, expected, and — with adequate dietary folate — almost always clinically silent."
Primary sources: ClinVar — MTHFR gene entries; Hickey et al., Genet Med 2013 (ACMG practice guideline); van der Pol et al., Eur J Hum Genet 2024 (DPWG guideline); Frosst et al., Nat Genet 1995; Weisberg et al., Mol Genet Metab 1998; OMIM 607093 — MTHFR.
What to look for in your raw data.
If you have downloaded raw genotype data from 23andMe, AncestryDNA, MyHeritage, or a VCF from clinical sequencing, you can locate your MTHFR genotype directly:
- rs1801133 is the SNP ID for C677T. 23andMe raw data reports the plus strand of GRCh37, where it shows G or A: MTHFR sits on the minus strand, so an A in the file is the T of C677T. GG = no copies, AG = one copy, AA = two copies of 677T.
- rs1801131 is the SNP ID for A1298C. On the plus strand it shows T or G, and a G in the file is the C of A1298C: TT = no copies, GT = one copy, GG = two copies of 1298C.
- Note: the C/T and A/C names come from the gene’s own strand, and other providers’ files may use either strand. If yours shows C or T at rs1801133, or A or C at rs1801131, it is on the gene’s strand and you can read C677T and A1298C directly; G or A, and T or G, mean the plus strand described above.
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