rs11627387 — MTHFD1

Intronic variant in the cytoplasmic trifunctional folate enzyme MTHFD1, associated with increased risk of congenital heart defects and neural tube defects — particularly under low dietary folate conditions

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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, 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 MTHFD1 (GRCh38 chr14:64,457,258; NC_000014.9:g.64457258G>A). As an intronic SNP, rs11627387 does not change the encoded protein sequence.

The Evidence

Two independent case-control studies from the same research group establish the A allele's association with birth defects. Zhu et al. 201222 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. 201233 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)44 (Feng et al. 2022, PMID 35838408), consistent with MTHFD1 influencing methylation-dependent neurodevelopment.

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.

Interactions

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.

Nutrient Interactions

folate increased_need
choline increased_need

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal

Standard MTHFD1 folate processing

You carry two copies of the G allele at rs11627387, the common reference genotype. About 52% of people globally carry this genotype; it is most common in European and Latino populations.

AG One Risk Allele Intermediate

Mildly reduced MTHFD1 haplotype efficiency; folate sufficiency is important

The strongest evidence for risk comes from studies examining embryonic outcomes under conditions of low maternal folate — the gene- nutrient interaction is the key finding, not the variant in isolation.

AA Two Risk Alleles High Risk

Homozygous MTHFD1 risk haplotype; folate and choline optimization are high priority

The gene-folate interaction is the most actionable element: studies consistently show that adequate maternal folate intake substantially reduces the elevated risk associated with this genotype.

Outside of reproduction, the same pathway supports nucleotide synthesis in rapidly dividing adult tissues and methylation capacity. The 2022 cognitive study suggests that under environmental stressors (fluoride exposure), GG carriers showed better cognitive outcomes than AA carriers, pointing to a broader role of MTHFD1 haplotype in methylation-sensitive neurodevelopmental processes.