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MTHFS Gene and Folate Metabolism: What Your Genotype Means for Methylation and Cellular Health

The MTHFS gene is a key part of folate metabolism. It converts 5-formyltetrahydrofolate (5-FTHF) into 5,10-methenyltetrahydrofolate (5,10-MTHF), a step that helps keep the folate cycle moving and supports the methylation processes your cells rely on. Methylation is important for regulating gene expression, detoxification, DNA synthesis, and many other cellular functions.

Changes in MTHFS activity can influence how efficiently folates are cycled and how available methyl groups are for critical reactions. Depending on your genotype, MTHFS activity may be lower, intermediate, or higher, which can affect folate balance, homocysteine levels, and overall methylation capacity. Below you will find plain-language explanations of the three possible genotypes for the rs6495446 variant and practical steps to support folate-related pathways.

Quick overview: Why MTHFS matters

  • MTHFS converts 5-formyl-THF to 5,10-methenyl-THF, helping maintain folate cycle flow.
  • Proper folate cycling supports DNA synthesis, repair, and methylation reactions throughout the body.
  • Altered MTHFS activity can lead to accumulation of 5-formyl-THF, which can inhibit other folate enzymes.
  • When folate cycling is affected, homocysteine may rise and extra support for active folate and B vitamins may be helpful.

Genetic interpretations

Two effect alleles (TT) — lower MTHFS transcription

Carrying two copies of the effect allele (TT) at rs6495446 is associated with lower MTHFS transcription compared with the CC genotype. Lower MTHFS activity may reduce conversion of 5-formyl-THF to 5,10-methenyl-THF, allowing 5-formyl-THF to build up. Accumulated 5-formyl-THF can inhibit other enzymes in the folate cycle, potentially decreasing the production of active folate derivatives needed for DNA synthesis and methylation.

Possible downstream effects:

  • Reduced generation of active folate forms such as 5-MTHF
  • Higher risk of impaired methylation and elevated homocysteine if other cofactors are suboptimal
  • Increased reliance on dietary or supplemental active folate and B vitamins to support methylation
One effect allele (CT) — intermediate MTHFS transcription

Carrying one effect allele (CT) generally gives intermediate MTHFS transcription and enzyme activity, falling between the TT and CC patterns. With intermediate activity, folate cycle function and methylation capacity are often normal, but they can be influenced by nutrition, lifestyle, and the activity of other folate-related genes.

Considerations:

  • Nutritional status of folate and B vitamins can shift your balance toward normal or mildly affected methylation.
  • Monitoring homocysteine and addressing other folate pathway factors can help maintain healthy methylation.
No effect alleles (CC) — higher MTHFS transcription

Carrying two copies of the non-effect allele (CC) is associated with increased MTHFS transcription and enzyme activity. Higher MTHFS activity supports efficient conversion of 5-formyl-THF to 5,10-methenyl-THF, preventing buildup of 5-formyl-THF and reducing inhibition of other pathway enzymes. This supports the generation of active folate derivatives needed for DNA synthesis and methylation.

Typical implications:

  • Generally favorable folate cycle flux and methylation capacity, assuming other folate enzymes and nutrient cofactors are healthy
  • Lower likelihood of folate-related inhibition that raises homocysteine, compared to lower-activity genotypes

Diet and nutrition recommendations

Tailor intake of folate and B vitamins to support folate cycle balance and methylation. These suggestions are educational; consult your healthcare provider before making major changes.

  • Prioritize natural folate from foods: leafy green vegetables, asparagus, Brussels sprouts, legumes, and avocado.
  • Consider food sources of active folate equivalents: fermented foods and certain fortified products may contain bioavailable folates.
  • Include foods rich in B2 (riboflavin), B6 (pyridoxine), and B12 (cobalamin) to support cofactors in one-carbon metabolism: eggs, dairy, lean meats, fatty fish, nuts, seeds, and whole grains.
  • Maintain adequate choline intake from eggs, liver, soybeans, and cruciferous vegetables to support methylation pathways that complement folate.
  • Limit excessive alcohol intake, which can interfere with folate absorption and folate-dependent reactions.

Supplement considerations

Supplements may help if diet alone is insufficient or if genetic and clinical indicators suggest reduced folate function. Discuss with your healthcare provider before starting supplements.

  • 5-MTHF (L-methylfolate): the active folate form that bypasses some folate cycle steps. Useful when MTHFS activity is decreased or when other folate enzymes are affected.
  • Vitamin B12 (methylcobalamin): supports methylation and homocysteine conversion; particularly important if you follow a vegetarian or vegan diet.
  • Vitamin B6 (pyridoxal-5-phosphate if available): supports enzymes in one-carbon metabolism and homocysteine breakdown.
  • Riboflavin (B2): a cofactor for enzymes that help maintain methylation balance.
  • Balanced B-complex: helpful for overall support when multiple B vitamin needs are indicated.
  • Choline and betaine: may support methylation through alternate pathways, particularly in people with compromised folate metabolism.

Lifestyle and monitoring

  • Regularly assess blood markers when indicated: serum folate, red blood cell folate, serum vitamin B12, and plasma homocysteine can help clarify functional status.
  • Work with your healthcare provider to interpret test results and adjust diet or supplements.
  • Maintain a balanced diet rich in folate and B vitamins and manage alcohol intake.
  • Manage stress, sleep, and physical activity: chronic stress and poor sleep can affect methylation and overall metabolic health.

When to talk to your healthcare provider

  • If blood tests show elevated homocysteine, low folate, or low B12
  • If you are pregnant, planning pregnancy, or have fertility concerns — folate status is especially important
  • If you have chronic health conditions that affect nutrient absorption or metabolism
  • Before starting or changing any supplement regimen, especially if you take medications that interact with folate or B vitamins

Limitations and important note

PlexusDx provides educational information about genetic predispositions only and does not provide medical advice. Genetic variants like rs6495446 are one piece of a larger health picture that includes diet, lifestyle, environment, and other genes. Always consult with your healthcare provider or a qualified clinician to interpret genetic results and to create a personalized plan based on your medical history, symptoms, medications, and lab results.