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MTHFD1 and Your Folate Metabolism: What Your Genotype Means for Health

The MTHFD1 gene encodes a multifunctional enzyme central to the folate cycle. It helps convert one-carbon folate derivatives that are essential for DNA synthesis, repair, and the supply of methyl groups used in many biochemical reactions, including remethylation of homocysteine to methionine. Variations in MTHFD1 can affect enzyme efficiency, which in turn can influence methylation capacity, homocysteine levels, and the body’s demand for folate and choline.

Why this matters

  • Folate derivatives produced by MTHFD1 are required for DNA building blocks and methylation reactions that regulate gene expression and detoxification.
  • Reduced MTHFD1 activity can raise the need for dietary folate, active folate forms, and certain B vitamins.
  • When MTHFD1 function is lower and choline intake is low, there can be a higher risk for folate-sensitive outcomes such as neural tube defects, fertility challenges, and altered homocysteine handling.

Genetic interpretation (rs2236225)

Two effect alleles (AA)

If you have the AA genotype you carry two copies of the effect allele. This is associated with reduced MTHFD1 enzyme activity. Reduced activity may limit availability of 5,10-methylenetetrahydrofolate and downstream 5-methyltetrahydrofolate, which support both nucleotide synthesis and methyl group donation. Potential consequences include higher homocysteine, lower methylation capacity, and increased requirement for activated folate (for example 5-MTHF), B2, B6 and B12, and dietary choline to maintain normal physiology. Consider monitoring folate status and homocysteine during pregnancy planning and periods of high metabolic demand.

One effect allele (AG)

If you have the AG genotype you carry one copy of the effect allele and one non-effect allele, producing intermediate MTHFD1 activity. Under normal conditions your folate and methylation pathways may function adequately, but efficiency can decline when folate intake is low, during illness, stress, pregnancy, or other times of increased demand. Supporting folate intake with foods and active B vitamins can help preserve methylation and nucleotide synthesis.

Zero effect alleles (GG)

If you have the GG genotype you carry two copies of the non-effect allele, which is generally associated with normal MTHFD1 activity. Folate processing, DNA synthesis, and homocysteine remethylation are likely efficient under typical dietary conditions, and your baseline risk for folate-related metabolic imbalance is lower. Standard dietary guidance for folate and choline still applies.

Dietary recommendations

Focus on whole foods that supply folate, choline and the B vitamins that support methylation and one-carbon metabolism.

  • Folate-rich foods: dark green leafy vegetables (spinach, kale), asparagus, Brussels sprouts, avocado, legumes, and oranges.
  • Active folate sources: fermented foods and some fortified foods provide folinic acid or folate; for people with reduced MTHFD1 activity, bioactive folate (5-MTHF) may be a consideration under provider guidance.
  • Choline-rich foods: eggs (yolks), beef liver, soybeans, chickpeas, and cruciferous vegetables support alternate methyl group pathways when folate is limited.
  • B vitamin foods: lean meats, fish, dairy, nuts, seeds, whole grains, and fortified cereals supply B2 (riboflavin), B6 and B12 important for one-carbon metabolism.
  • Limit excessive alcohol and highly processed foods that can impair folate status.

Supplement recommendations (discuss with your healthcare provider)

  • Folate: For those with reduced MTHFD1 activity, a supplement containing active folate (5-MTHF) may be preferred over folic acid. Dose and necessity should be individualized.
  • B vitamins: Balanced B-complex with adequate B2 (riboflavin), B6 (pyridoxine or pyridoxal-5-phosphate), and B12 (methylcobalamin) supports enzyme cofactors in one-carbon metabolism.
  • Choline: Consider supplementation or increased dietary choline if intake is low, especially during pregnancy planning and pregnancy.
  • Monitoring and targeted supplementation: If homocysteine is elevated, a provider may recommend a combination of B vitamins to help lower levels.

Recommended lifestyle and practical tips

  • Plan pregnancies with attention to folate and choline status. If you are pregnant or planning pregnancy, consult your healthcare provider about prenatal vitamins and appropriate folate form and dose.
  • Maintain a balanced diet with regular servings of leafy greens, legumes, eggs, and lean protein to provide natural folate and choline.
  • Avoid smoking and limit alcohol, both of which can impair folate status and increase homocysteine.
  • Manage stress, get regular sleep, and stay active. Periods of high stress or illness increase demands on methylation and nucleotide synthesis.
  • If you are on medications that affect folate or B vitamin absorption, review these with your provider to adjust intake as needed.

Blood tests and monitoring

  • Consider measuring plasma or serum folate and red blood cell folate to evaluate folate stores when indicated.
  • Plasma homocysteine is a useful functional marker of one-carbon metabolism and can indicate increased need for folate or B vitamins.
  • Vitamin B12 and B6 status testing is useful when homocysteine is elevated or when supplementing B vitamins.

Other considerations

  • Genetic effects are one piece of the puzzle. Diet, lifestyle, medications, and other genes that affect folate, B vitamins, and choline all shape outcomes.
  • If you are pregnant or planning pregnancy, small changes in folate or choline intake can be important for neural development; coordinate supplementation with your healthcare provider.
  • People with dietary restrictions, vegetarian or vegan diets, or malabsorption conditions may need extra attention to B12, folate, and choline.

Important disclaimer

PlexusDx does not provide medical advice. This information is educational and describes genetic predispositions related to MTHFD1 and folate metabolism. Genetic results do not diagnose any condition. Always review these findings and any changes to diet, supplements, or medical care with your healthcare provider before starting or stopping supplements, especially if you are pregnant, breastfeeding, taking medications, or have a chronic health condition.