Evidence check: MTHFR in the context of fatigue

The claim that MTHFR variants directly cause fatigue is weakly supported by evidence. MTHFR (C677T, A1298C) affects folate metabolism and can elevate homocysteine – a risk factor for cardiovascular and neurological issues. However, large studies (e.g., meta-analyses) show no consistent link between MTHFR polymorphisms and general fatigue. Most individuals with MTHFR variants are asymptomatic. Anecdotal reports of improvement after supplementation (e.g., methylfolate) are not backed by randomized controlled trials. Caution: many commercial DNA tests overstate clinical significance. An MTHFR test alone is not recommended for fatigue workup; measuring homocysteine, vitamin B12, and folate levels is more informative. Evidence is mixed: mechanistically plausible but clinically insufficient for routine diagnosis.