What role does MTHFR play in fatigue?

MTHFR encodes an enzyme that converts folate into its active form. Variants like C677T can reduce enzyme activity, potentially raising homocysteine levels, which has been linked to fatigue in some observational studies. However, the evidence is mixed: many studies find only weak or no association, especially when nutrient status is adequate. Direct-to-consumer tests often overstate the role of MTHFR in fatigue. A positive result alone does not explain fatigue; more common causes like iron deficiency, thyroid issues, or poor sleep should be ruled out first. Supplementing with methylfolate without a confirmed deficiency is not recommended and may cause side effects. Evidence: human-moderate.