rs11627387 — MTHFD1

MTHFD1 rs11627387 — Folate Efficiency and Congenital Risk

MTHFD1 encodes the cytoplasmic trifunctional C1-tetrahydrofolate synthase¹¹ cytoplasmic trifunctional C1-tetrahydrofolate synthase
a single protein carrying three enzymatic domains: methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetase — three consecutive reactions that interconvert folate one-carbon carriers in the cytoplasm. This central enzyme feeds activated one-carbon units into purine synthesis, thymidylate synthesis, and the remethylation of homocysteine to methionine. rs11627387 is an intronic variant in strong linkage disequilibrium with nearby functional variants on the same chromosome 14 haplotype, and its A allele has been independently associated with congenital heart and neural tube defects in case-control studies.

The Mechanism

The variant lies within intron 18 of MTHFD1 (GRCh38 chr14:64,457,258; NC_000014.9:g.64457258G>A). As an intronic SNP, rs11627387 does not change the encoded protein sequence but is in linkage disequilibrium with functional coding variants in the R653Q region²² linkage disequilibrium with functional coding variants in the R653Q region
rs2236225 encodes the R653Q missense change; rs11627387 and rs2236224 are intronic tag SNPs on the same haplotype; the Q allele impairs synthetase domain activity, meaning it captures haplotype-level variation in MTHFD1 enzymatic output. When the synthetase domain is impaired, the production of 10-formyl-THF (required for purine ring synthesis and thymidylate synthesis) is reduced. During embryogenesis — when cells are dividing rapidly and nucleotide demand is maximal — this bottleneck is most consequential.

The Evidence

Two independent case-control studies from the same research group establish the A allele's association with birth defects. Zhu et al. 2012³³ Zhu et al. 2012
Gene variants in the folate-mediated one-carbon metabolism pathway as risk factors for conotruncal heart defects. Am J Med Genet A, 2012 found the A allele conferred a 1.7-fold increase in conotruncal heart defect risk in both Hispanic mothers (OR 1.7, 95% CI 1.1–2.5) and infants (OR 1.7, 95% CI 1.2–2.3), suggesting both maternal folate metabolism and embryonic genotype contribute independently. Etheredge et al. 2012⁴⁴ Etheredge et al. 2012
Maternal and infant gene-folate interactions and the risk of neural tube defects. Am J Med Genet A, 2012 showed that among infants with the A allele born to mothers with low folate intake, the odds ratio for neural tube defects rose to 4.25 (80% CI 2.33–7.75) — the strongest gene-folate interaction identified in that dataset. A 2022 study in Chinese children exposed to endemic fluoride found GG homozygotes showed superior cognitive outcomes compared to AA carriers under high-fluoride conditions (Feng et al. 2022, PMID 35838408)⁵⁵ (Feng et al. 2022, PMID 35838408), consistent with MTHFD1 influencing methylation-dependent neurodevelopment.

A meta-analysis of the closely linked rs2236225 (G1958A / R653Q) variant across 9 studies (4,302 NTD cases, 4,238 controls) found pooled OR 1.17 (p=0.001) for maternal carriers; Jiang et al. 2014⁶⁶ Jiang et al. 2014. Both rs11627387 and rs2236225 are on the same risk haplotype and should be interpreted together.

Practical Actions

The gene-folate interaction is the central actionable insight: the A allele's risk appears to be substantially modified by folate status. Women planning pregnancy who carry the A allele should prioritize preconception folate sufficiency using methylfolate (5-MTHF) rather than synthetic folic acid, which bypasses the conversion step. Choline is also relevant because the MTHFD1 pathway intersects with the choline-betaine methyl-donation route — impaired MTHFD1 increases dependence on choline for one-carbon unit supply.

Interactions

rs11627387 is in linkage disequilibrium with rs2236225 (MTHFD1 R653Q) and rs2236224 (intronic tag) — all three are on the same chromosome 14 risk haplotype. The functional variant is R653Q (rs2236225), which reduces the synthetase domain's stability via TRIM21-mediated ubiquitination. Interactions with MTHFR C677T (rs1801133) and MTR (rs1805087) are biologically plausible through convergent demand on the cytoplasmic folate pool, but no published study has quantified the combined rs11627387 + MTHFR effect directly. Compound MTHFR + MTHFD1 haplotype studies are warranted, especially for preconception counseling.