rs1801133 — MTHFR C677T (Ala222Val)
Drug response / Risk factor · ~32% global allele frequency (T allele)
rs1801133 causes a thermolabile MTHFR enzyme with ~70% reduced activity in TT homozygotes. This leads to elevated homocysteine levels, impaired folate metabolism, and altered methylation capacity. It is the most studied pharmacogenomic variant worldwide.
Molecular Mechanism
The Ala222Val substitution destabilizes the FAD-binding domain of MTHFR at physiological temperatures, reducing 5-methyltetrahydrofolate production. This impairs methionine synthase activity and disrupts the entire one-carbon metabolism cycle.
Peptide Therapeutic Relevance
Peptides stabilizing the FAD-binding domain or mimicking 5-MTHF function are computational targets. PepFold maps the variant to the MTHFR protein structure and generates candidates targeting the affected functional region.
Gene: MTHFR (Methylenetetrahydrofolate Reductase)
Catalyzes conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary circulating form of folate. Essential for homocysteine remethylation and one-carbon metabolism.
Chromosome 1p36.22
Condition: Hyperhomocysteinemia (MTHFR-related)
Elevated blood homocysteine due to MTHFR variants (C677T, A1298C) affecting folate metabolism. Associated with cardiovascular disease, neural tube defects, and potential cognitive effects. The most common pharmacogenomic condition worldwide.
Prevalence: 10-15% of most populations are TT homozygous for C677T; up to 25% in some Mediterranean populations
Related Variants
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