Are MTHFD1 rs2236225 and MTRR rs1801394 variants linked to altered folate/B12 one-carbon metabolism?

Genomic variations in the one-carbon metabolic pathway can significantly alter nutrient processing, cofactor recycling, and cellular methylation capacity.

Molecular mechanisms and cellular impact

• MTHFD1 rs2236225 (G1958A): This variant alters the 10-formyl-THF synthetase domain of the cytosolic MTHFD1 enzyme. The resulting protein is thermolabile, exhibiting a 36% reduction in half-life at 42°C. In cell models, this structural instability translates to an approximate 25% to 26% reduction in de novo purine synthesis.
• MTRR rs1801394 (A66G): This polymorphism alters the flavin mononucleotide (FMN)-binding domain of methionine synthase reductase, decreasing its binding affinity for the methionine synthase (MTR)-cobalamin complex. This protein-protein interface disruption reduces in vivo enzyme activity up to four-fold, slowing down the reactivation of oxidized cob(II)alamin to active methylcobalamin.

Clinical and metabolic implications

• Impaired remethylation: Both variants disrupt downstream homocysteine remethylation to methionine. While MTHFD1 rs2236225 acts as an independent predictor of plasma homocysteine, MTRR rs1801394 functions as a sensitizing variant that elevates homocysteine primarily during B-vitamin deficiency or when co-occurring with other pathway mutations like MTHFR C677T.
• Nutritional stabilization: The physiological consequences of these variants are highly dependent on nutritional cofactors. Folate restriction exacerbates metabolic perturbation in MTHFD1 1958AA carriers, whereas adequate active folate pentaglutamate binds and physically stabilizes the thermolabile enzyme in vitro, buffering against the genetic defect.

Bottom line

• Bottom line: The MTHFD1 rs2236225 and MTRR rs1801394 variants are directly linked to altered one-carbon metabolism, predisposing carriers to reduced purine synthesis and elevated homocysteine through compromised enzyme stability and active B12 recycling, respectively—effects that are highly sensitive to overall folate and cobalamin status.