THE PLAIN-LANGUAGE EXPLAINER
What Is MTHFR A1298C?
MTHFR A1298C is one of the two common inherited variants of a gene at the centre of folate biochemistry. This page says exactly what the enzyme does, exactly what the variant changes, and exactly how common it is — with the primary sources attached. Nothing here is medical advice.
First, the enzyme: what MTHFR does
MTHFR — 5,10-methylenetetrahydrofolate reductase, EC 1.5.1.20 — is a cytosolic enzyme that runs on FAD, a riboflavin-derived cofactor. It catalyses one essentially irreversible reaction: the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-methylTHF). That product is the predominant circulatory form of folate and the carbon donor for the re-methylation of homocysteine to methionine.[4][8]
From methionine, the cell builds SAM — S-adenosylmethionine, the universal methyl donor for DNA, histone, protein and phospholipid methylation. And the cycle talks back: SAM is an allosteric inhibitor of MTHFR itself, binding the enzyme’s C-terminal regulatory domain. Hold that thought — it is the domain this site’s variant lives in.[69][9]
Then, the variant: what A1298C is
A1298C is a single-base transversion — an A swapped for a C — in exon 7 of the MTHFR gene. Its database name is rs1801131, its modern notation c.1286A>C, and its protein consequence p.Glu429Ala: the glutamate at residue 429 becomes an alanine. Legacy names “A1298C”, “1298A→C” and “E429A” all refer to the same change.[11][12]
Residue 429 sits in the C-terminal regulatory domain — the SAM-binding, allosteric part of the protein — not in the N-terminal catalytic core where the better-known C677T variant (Ala222Val) does its damage. That location is the single most useful fact for interpreting everything written about A1298C: it is a variant of the enzyme’s control region, not of its active machinery.[9][8]
It was found in 1998, twice, independently: by the Nijmegen group of van der Put, hunting through neural-tube-defect families, and by Weisberg and colleagues in Montreal, measuring enzyme activity in a Canadian sample. The 1298C allele sat at frequency 0.33 in the Dutch sample, and about 10% of Canadians were 1298CC homozygotes.[5][6]
What it does to the enzyme — and the famous caveat
In lymphocyte extracts, homozygous 1298CC carriers run at roughly 60% of control MTHFR activity; the 1998 discovery study measured the decrease as most pronounced in homozygotes (ANOVA P<.0001). In recombinant expression, the 1298 mutant retained 68% ± 5.0 of wild-type activity — against 45% ± 10.8 for the 677 mutant — and, unlike C677T, it is not thermolabile.[5][6][7]
The caveat this site reports prominently: when highly purified recombinant human Glu429Ala MTHFR was characterised in 2001, it was “indistinguishable from the wild-type enzyme” in its biochemical properties. The cellular activity reduction is real in lymphocyte extracts, but the purified protein behaves normally — the in-vivo mechanism is less destructive than C677T’s, and less understood.[8]
How common it is
Very common, and unevenly distributed. The table gives gnomAD exome allele frequencies for the 1298C allele (rs1801131, retrieved via Ensembl REST on 2026-08-09); the carrier and homozygote columns are Hardy-Weinberg arithmetic (2pq and q²) from those frequencies, not direct genotype counts.[14]
| POPULATION | 1298C ALLELE | CARRIERS (AC) | HOMOZYGOTES (CC) |
|---|---|---|---|
| Global | 0.307 | ≈42.6% | ≈9.4% |
| European (non-Finnish) | 0.313 | ≈43% | ≈9.8% |
| European (Finnish) | 0.314 | ≈43.1% | ≈9.9% |
| Ashkenazi Jewish | 0.292 | ≈41.3% | ≈8.5% |
| Middle Eastern | 0.373 | ≈46.8% | ≈13.9% |
| South Asian | 0.411 | ≈48.4% | ≈16.9% |
| East Asian | 0.205 | ≈32.6% | ≈4.2% |
| African / African-American | 0.157 | ≈26.5% | ≈2.5% |
| Admixed American | 0.167 | ≈27.8% | ≈2.8% |
The primary-literature anchors agree across a quarter-century: 0.33 in the 1998 Dutch discovery sample, about 10% 1298CC in the 1998 Canadian sample.[5][6]
What it means — and what it does not
Carrying A1298C — even two copies — is a common human state, shared with hundreds of millions of people, and the variant alone is not associated with higher homocysteine or lower folate in the discovery and family-study data.[5][7]
Where it becomes scientifically interesting is in combination (compound heterozygosity with C677T), in low-folate contexts, and in the open association literature — most of which is null. The comparison page covers the first; the homocysteine page covers the second; the research journal covers the third.
Genotype results and supplementation questions belong with a qualified clinician who knows the full clinical picture. This site makes the published evidence readable; it does not direct anyone’s care.