rs1801131 — MTHFR A1298C

MTHFR A1298C — The Second Methylation Variant

The A1298C variant (rs1801131) is the second most-studied MTHFR variant. While C677T gets most of the attention, A1298C also affects MTHFR enzyme activity, though through a different mechanism and with a milder effect.

The Mechanism

The A1298C variant causes a glutamic acid-to-alanine substitution ¹¹ Glutamic acid-to-alanine substitution at position 429 of the protein (p.Glu429Ala) at position 429 of the MTHFR protein. This position is in the regulatory domain of the enzyme (whereas C677T affects the catalytic domain), which is why its effect on enzyme activity is milder. The GG genotype ²² CC on the coding strand — 23andMe reports the complementary strand reduces MTHFR activity by about 30-40%, compared to the 70% reduction seen with C677T TT. ClinVar classifies this variant as benign on its own, as neither homozygotes nor heterozygotes show significantly elevated homocysteine in most studies.

Compound Heterozygosity

The most clinically relevant scenario involving A1298C is compound heterozygosity ³³ Compound heterozygosity: carrying one variant copy at each of two different positions in the same gene — carrying one variant at C677T (AG) AND one variant at A1298C (GT). This combination can reduce MTHFR activity to a degree similar to being homozygous for C677T alone (about 40-50% reduction). If you carry variants at both positions, you should pay closer attention to your folate and methylation status.

The Evidence

Studies show that A1298C alone has a weaker association with elevated homocysteine⁴⁴ weaker association with elevated homocysteine
Population studies show A1298C alone has minimal effect on homocysteine levels compared to C677T. However, compound heterozygotes⁵⁵ compound heterozygotes
Weisberg I et al. Compound heterozygosity of C677T and A1298C reduces MTHFR activity, 2001 (one copy of each) show homocysteine levels intermediate between normal and C677T homozygous individuals. This matters because many people who are "only heterozygous" for C677T may actually have meaningful methylation impairment if they also carry an A1298C variant.

Practical Considerations

If you are GG at A1298C, treat your methylation support similarly to having moderate C677T impairment. If you are compound heterozygous (AG at C677T + GT at A1298C), consider the same approach as for C677T TT: methylfolate supplementation, adequate B12 and B2, and periodic homocysteine monitoring.

Interactions

The A1298C variant interacts with C677T (rs1801133) in compound heterozygosity. It also interacts with SLC19A1 (rs1051266) for overall folate pathway efficiency and with MTHFD1 (rs2236225) for one-carbon metabolism capacity.