rs1805087 — MTR A2756G

MTR — The Methionine Synthase

Methionine synthase (MTR), also known as MS, catalyzes the final step that converts homocysteine back to methionine using methylcobalamin (active B12) as a cofactor and methylfolate as the methyl donor. This reaction sits at the crossroads of the methylation cycle and is essential for keeping homocysteine levels in check.

The Mechanism

The A2756G variant (rs1805087) causes an aspartic acid-to-glycine substitution ¹¹ Aspartic acid-to-glycine substitution at position 919 of the protein (p.Asp919Gly) at position 919 of the MTR protein. The G allele produces an enzyme with altered activity that tends to favor the active (reduced) state of B12. Paradoxically, this may seem beneficial, but the altered enzyme kinetics can lead to disrupted methylation cycling under certain conditions, particularly when B12 or folate levels are suboptimal. ClinVar classifies this variant as benign given its population frequency.

The Folate Trap

MTR is at the center of what biochemists call the "methyl-folate trap." ²² When MTR is impaired, methylfolate accumulates unusably — a functional folate deficiency despite normal blood levels When MTR activity is impaired, methylfolate accumulates because it cannot donate its methyl group to homocysteine. This creates a functional folate deficiency even when total folate levels appear adequate. Understanding your MTR status helps explain why some people with "normal" folate levels still show signs of impaired methylation.

Clinical Significance

Studies have linked the G allele to altered homocysteine metabolism, though the effects are typically modest. A meta-analysis³³ meta-analysis
Zhao D et al. MTR A2756G and cancer risk, 2010 examined the variant's association with cancer risk across multiple study types. The variant becomes more clinically relevant when combined with MTRR variants (which affect B12 reactivation) and MTHFR variants (which affect methylfolate production). This triad of enzymes works as a coordinated system ⁴⁴ MTR + MTRR + MTHFR form a triad: folate provides the methyl group, B12 carries it, and MTRR keeps B12 active, and weakness at multiple points compounds the effect.

Practical Implications

If you carry the G allele, ensuring generous B12 intake is important since your MTR enzyme has altered B12 handling. Active B12 forms are preferred. Combined with adequate folate (as methylfolate if you have MTHFR variants), this supports optimal homocysteine conversion and methylation cycling.

Interactions

MTR works directly with MTRR (rs1801394) — MTR performs the reaction and MTRR reactivates it. Both interact with MTHFR (rs1801133) as the provider of the methylfolate substrate.