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MTHFD1L and Your Folate-Methylation Pathways: What Your Genotype Means

The MTHFD1L gene helps produce an enzyme that supports the mitochondrial folate pathway. This enzyme helps convert different forms of tetrahydrofolate and generates formate, which supplies one-carbon units to the cytoplasmic folate cycle. Those one-carbon units are essential for methylation, DNA synthesis, neurotransmitter production, and recycling homocysteine. Variations in MTHFD1L can change enzyme efficiency, which may affect methyl donor availability and homocysteine levels. Below is an easy to understand guide to how different genotypes can influence health and practical steps you can take to support these pathways.

How reduced MTHFD1L activity can affect the body

  • Lower production of formate and one-carbon units can reduce availability of methyl donors such as S-adenosylmethionine.
  • Impaired methylation may affect gene expression, neurotransmitter balance, and detoxification processes.
  • Less efficient homocysteine recycling can lead to higher homocysteine levels, a marker associated with cardiovascular and cognitive risk when persistently elevated.
  • When enzyme function is reduced, ensuring adequate folate and B-vitamin status becomes more important to maintain metabolic balance.

Practical recommendations overview

  • Diet: Focus on folate rich foods and a balanced B-vitamin intake.
  • Supplements: Consider active folate forms and B vitamins if dietary intake is limited or if lab tests show deficiencies.
  • Blood tests: Check homocysteine, serum folate, RBC folate, B12 and methylmalonic acid as indicated.
  • Lifestyle: Support methylation with regular physical activity, balanced sleep, stress management, and moderate alcohol use.
  • Consult your healthcare provider: PlexusDx does not provide medical advice. Always review test results and changes with a qualified clinician before starting new supplements or treatments.

Genetic Interpretation

Two effect alleles (AA) — reduced MTHFD1L activity

If your genotype is AA for rs11754661 you carry two copies of the effect allele. This is associated with reduced efficiency of the MTHFD1L enzyme. Reduced enzyme activity can limit production of formate and therefore reduce one-carbon units supplied to the cytoplasmic folate cycle. That may result in:

  • Higher risk of impaired methylation and disrupted DNA synthesis under low folate conditions
  • Increased likelihood of elevated homocysteine if folate and B12 status are inadequate
  • Potential effects on neurotransmitter synthesis and detoxification pathways

Recommendations if you have AA genotype

  • Diet: Prioritize leafy greens, legumes, asparagus, broccoli, beets, citrus and fortified whole grains to maximize dietary folate.
  • Supplements: Discuss with your clinician the use of active folate (5-MTHF) rather than folic acid, and consider a B complex that includes B2, B6 and methylcobalamin (active B12) if needed.
  • Blood tests: Monitor homocysteine, serum folate, RBC folate and B12 levels to assess status and response to interventions.
  • Lifestyle: Maintain regular exercise, adequate sleep and stress management to support methylation and cardiovascular health.
  • Medical review: Work with your healthcare provider before adding supplements, especially if you take medications or have medical conditions.
One effect allele (AG) — moderately reduced MTHFD1L activity

If your genotype is AG for rs11754661 you carry one effect allele and one non-effect allele. This is associated with moderately reduced MTHFD1L enzyme activity. Under normal circumstances these pathways usually function, but you may be more sensitive to low folate or B-vitamin intake. Possible implications include:

  • Subtle reductions in one-carbon availability when dietary intake is low
  • Greater likelihood that folate or B12 deficiencies will negatively affect methylation and homocysteine recycling
  • Need for attentive nutrition during physiological stress, pregnancy or illness

Recommendations if you have AG genotype

  • Diet: Ensure regular intake of folate rich foods and maintain balanced B-vitamin intake through diet.
  • Supplements: Consider low dose active folate (5-MTHF) and ensure adequate B12 if dietary intake is limited or lab tests indicate low levels. A complete B complex may be useful in times of increased need.
  • Blood tests: Periodic checking of homocysteine and folate markers can help detect early imbalances.
  • Lifestyle: Support overall metabolic health with consistent sleep patterns, physical activity and limiting alcohol which can impair folate status.
  • Medical review: Consult your healthcare provider to tailor supplement doses and monitor labs before changing therapies.
No effect alleles (GG) — typical MTHFD1L activity

If your genotype is GG for rs11754661 you carry two non-effect alleles. This pattern is generally associated with normal MTHFD1L enzyme activity. With adequate nutrition your folate and methylation pathways are likely to function effectively, supporting DNA synthesis and homocysteine recycling. Practical points:

  • Maintain a folate rich diet and balanced intake of B-vitamins to support ongoing methylation needs.
  • Routine monitoring of folate and B12 is reasonable if new symptoms or health changes occur.
  • Standard public health guidance around folate intake applies, especially for those planning pregnancy or who are pregnant.
  • If other genetic or health factors are present, individualized advice from your clinician remains important.

Dietary guidance

  • Focus on natural folate sources: dark leafy greens, legumes, Brussels sprouts, beets, asparagus, and citrus.
  • Include B12 sources if you eat animal products: fish, poultry, eggs and dairy. If vegan or low on animal foods, consider B12 supplementation.
  • Include riboflavin rich foods such as dairy, lean meats, and green vegetables since B2 supports folate metabolism.
  • Limit excessive alcohol and smoking which can deplete folate and impair methylation.

Supplement considerations

  • Active folate (5-MTHF) may be preferred when methylation support is needed; dosing should be personalized with professional guidance.
  • Methylcobalamin (active B12) is useful when B12 levels are low or absorption is a concern.
  • B6 and riboflavin (B2) support one carbon metabolism and can be part of a targeted B-complex.
  • Avoid high dose single nutrient changes without clinician oversight. Monitor labs when starting supplements.

Recommended blood tests and follow up

  • Plasma homocysteine to assess functional methylation and cardiovascular risk markers when indicated.
  • Serum folate and red blood cell folate for folate status.
  • Serum B12 and methylmalonic acid for B12 status.
  • Repeat tests after nutritional or supplement interventions as recommended by your provider.

Lifestyle tips to support methylation

  • Regular aerobic exercise and strength training help overall metabolic health.
  • Consistent sleep and stress reduction improve biochemical resilience.
  • Avoid smoking and limit alcohol to protect folate status.
  • Keep a balanced dietary pattern with whole foods, varied vegetables and lean proteins.

PlexusDx provides educational information about genetic predispositions only. This information does not constitute medical advice. Always discuss genetic results, test choices and any changes to diet, supplements, or medications with your healthcare provider before starting or stopping anything.