rs2236225 — MTHFD1 G1958A

MTHFD1 — The Choline Connection

MTHFD1 (methylenetetrahydrofolate dehydrogenase 1) is a trifunctional enzyme that processes dietary folates through three sequential reactions. It plays a central role in one-carbon metabolism ¹¹ One-carbon metabolism: a network of folate-dependent reactions that shuttle single carbon units for DNA synthesis and methylation, feeding into both nucleotide synthesis ²² For DNA repair and cell division — rapidly dividing cells like gut lining and blood cells are especially dependent and the methylation cycle.

The Mechanism

The G1958A variant (rs2236225) causes an arginine-to-glutamine substitution ³³ Arginine-to-glutamine substitution at position 653 of the protein (p.Arg653Gln) at position 653 of the MTHFD1 protein. The A allele produces a less thermostable enzyme that loses activity more readily at body temperature. This reduces the efficiency of folate processing, particularly the 10-formyltetrahydrofolate synthetase activity that is important for purine synthesis. While the enzyme retains normal substrate affinity, its reduced stability diminishes overall metabolic activity.

The Choline Compensation

What makes MTHFD1 especially interesting is its connection to choline. When MTHFD1 activity is reduced, your body compensates by drawing more heavily on choline as an alternative methyl donor ⁴⁴ The betaine pathway: choline is oxidized to betaine, which donates a methyl group directly to homocysteine, bypassing the folate cycle. This increases your dietary choline requirements significantly. Studies have shown that individuals with the AA genotype who consume low-choline diets are more likely to develop signs of choline deficiency, including fatty liver.

The Evidence

A landmark study by Kohlmeier et al.⁵⁵ Kohlmeier et al.
Kohlmeier M et al. PNAS 2005 — genetic variation in folate-mediated one-carbon transfer predicts susceptibility to choline deficiency demonstrated that the A allele is a risk factor for neural tube defects, independent of MTHFR status. A meta-analysis of nine studies⁶⁶ meta-analysis of nine studies
Shen H et al. MTHFD1 polymorphisms and neural tube defect susceptibility, 2014 with 4,302 NTD patients and 4,238 controls confirmed an increased risk of neural tube defects with the AA genotype (OR=2.63). Subsequent research confirmed that this variant increases choline requirements and that adequate choline intake can compensate for the reduced MTHFD1 activity.

Practical Implications

Egg yolks are the richest common dietary source of choline, providing about 150mg per yolk. Liver is even richer. If you carry the A allele, eating 2-3 egg yolks daily provides meaningful choline support. This is one of the most actionable nutrigenomics findings — a simple dietary change (eating more eggs) can compensate for a clear genetic limitation.

Interactions

MTHFD1 interacts with MTHFR (rs1801133, rs1801131) for overall folate pathway efficiency. It also interacts with PEMT (rs7946) — both variants increase choline requirements, and the combined effect can be substantial.