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rs2236225 — MTHFD1 G1958A

Folate processing enzyme — reduced stability increases choline need

Your genotype

AG — Reduced MTHFD1 stability — increased choline need

Your recommendations

  • Supplement with choline (CDP-choline or citicoline)
  • Prioritize choline-rich foods
  • Use methylfolate and increase egg yolk intake — MTHFR A1298C + MTHFD1 combined impairment
Learn more

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.

Nutrient Interactions

choline increased_need
folate impaired_conversion

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal Stability Normal

Normal MTHFD1 enzyme stability

Your MTHFD1 enzyme has normal stability. This enzyme helps process dietary folates. About 32% of Europeans share this genotype.

AG Reduced Stability Intermediate Your genotype

Reduced MTHFD1 stability — increased choline need

You carry one copy of this variant, which reduces MTHFD1 enzyme stability. This increases your need for dietary choline as an alternative methylation pathway. About 49% of people share this genotype.

AA Low Stability Reduced

Significantly reduced MTHFD1 — high choline need

You have two copies of this variant. Your MTHFD1 enzyme is less stable, meaning you rely more heavily on dietary choline for methylation support. About 19% of people share this genotype.

Your recommendations

Reduced MTHFD1 stability — increased choline need

Your genotype AG

Gene interactions affecting you

Supplement

Use methylfolate and increase egg yolk intake — MTHFR A1298C + MTHFD1 combined impairment

Heterozygous MTHFR A1298C combined with heterozygous MTHFD1 R653Q creates moderate sequential folate pathway impairment — methylfolate supplementation and increased dietary choline are more beneficial than folic acid alone.

MTHFR A1298C GT mildly reduces MTHFR regulatory domain activity (~15–20%). MTHFD1 AG produces intermediate enzyme stability, partly reducing upstream folate substrate supply. Combined, this represents moderate but meaningful one-carbon pathway impairment across two sequential steps.

Methylfolate: switch to 400 mcg L-methylfolate (5-MTHF) daily instead of folic acid. Folic acid requires full MTHFR activity to convert to active form; methylfolate bypasses this limitation.

Dietary choline: target 500–550 mg daily (above the standard 425–550 mg adequate intake to account for increased demand through the betaine compensation pathway). Prioritize 2–3 egg yolks daily (approximately 300–450 mg choline total), liver 1–2 times weekly, and regular servings of salmon and soybeans.

B12 and riboflavin: ensure 500–1000 mcg methylcobalamin daily and 2–3 mg riboflavin (B2) daily as supporting cofactors for the methylation cycle.

If you are or may become pregnant: discuss folate supplementation with your midwife or physician. This MTHFD1 variant was associated with OR 2.63 for neural tube defects in meta-analysis at AA homozygosity; the AG heterozygous intermediate warrants adequate methylfolate in the periconceptional period.

Combined evidence

Supplement

Supplement with choline (CDP-choline or citicoline)

Your genetic variants reduce the body's capacity for endogenous choline and phosphatidylcholine synthesis, increasing reliance on dietary choline supply. Affected pathways include methyl donor flux, de novo hepatic phosphatidylcholine synthesis, and betaine-dependent homocysteine remethylation.

Preferred supplemental forms: CDP-choline (citicoline) provides choline plus cytidine (a precursor to uridine), making it particularly well-utilized for brain phosphatidylcholine synthesis. Phosphatidylcholine (from sunflower lecithin, 1,200–2,400 mg/day) is an efficient hepatic form. Choline bitartrate (500–1,000 mg/day) is a lower-cost option. Alpha-GPC (glycerophosphocholine) is well-absorbed but primarily indicated for cognitive applications.

Dosing target: 450–550 mg/day total choline (dietary plus supplemental combined). Supplement with 400–550 mg phosphatidylcholine or choline bitartrate if diet does not reach this level. Prioritize dietary sources: 3+ egg yolks daily (~450 mg choline) is an efficient food-first strategy. Betaine (trimethylglycine, 1–3 g/day) is a complementary supplement that directly supports homocysteine remethylation.

Dietary sources: egg yolks (~147 mg each), beef liver (~418 mg per 3 oz), salmon (~187 mg per 3 oz), edamame (~164 mg per cup), soybeans. Two eggs plus one serving of salmon covers approximately 480 mg of choline.

During pregnancy: fetal demand on top of your reduced endogenous synthesis makes adequate intake critical — ensure 450–550 mg/day from combined food and supplementation throughout pregnancy and breastfeeding. Most prenatal vitamins contain little or no choline; add separately.

Monitor liver enzymes (ALT, AST) annually if dietary choline is consistently low, as choline deficiency specifically causes hepatic steatosis.
Diet

Prioritize choline-rich foods

Your genetic profile reduces your ability to produce choline internally and increases your dietary choline requirements for methylation and liver function.

Aim for 500–600 mg choline daily from food sources. The best sources are: - Egg yolks: ~150 mg each (2–3 daily is ideal) - Liver: ~350 mg per 3 oz serving - Salmon: ~75 mg per serving - Soybeans/edamame: ~55 mg per half cup

Your genetics reduce internal phosphatidylcholine synthesis and increase choline demand as an alternative methyl donor. This makes you more dependent on dietary intake than the general population for both methylation support and liver protection.

If you can't consistently eat 2–3 egg yolks daily, consider a phosphatidylcholine or choline bitartrate supplement (300–500 mg).