Is MTHFR p.Ala116= (c.348C>G) pathogenic?

MTHFR p.Ala116= (c.348C>G) is classified Likely benign in MTHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-22). Absent from gnomAD v4.1; Associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency.

What condition is associated with MTHFR p.Ala116= (c.348C>G)?

MTHFR p.Ala116= (c.348C>G) is associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

How common is MTHFR p.Ala116= (c.348C>G) in the general population?

MTHFR p.Ala116= (c.348C>G) is absent from gnomAD v4.1 (gnomAD).

MTHFR p.Ala116=

Q: How is Homocystinuria due to methylene tetrahydrofolate reductase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.348C>G · rs144921426 · VCV2007079

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

homocystinuria due to methylene tetrahydrofolate reductase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.1
Overall
CADD	0.153	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MTHFR
Protein: p.Ala116=
Coding: c.348C>G
MANE Select: NM_005957
dbSNP: rs144921426
Type: single nucleotide variant
Location: chr1:11801288 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 116: an α-helix

Full MTHFR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

homocystinuria due to methylene tetrahydrofolate reductase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Homocystinuria due to methylene tetrahydrofolate reductase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

MTHFR p.Ala116Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MTHFR c.1166+1G>T Likely pathogenic ★★ same condition
MTHFR c.1166+5G>C Pathogenic/Likely pathogenic ★★ same condition
MTHFR c.1347+1G>A Pathogenic ★★ same condition
MTHFR c.1348-1G>C Likely pathogenic ★★ same condition
MTHFR c.1530+1G>A Likely pathogenic ★★ same condition
MTHFR c.1530+1G>T Likely pathogenic ★★ same condition
MTHFR c.1632+2T>G Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mthfr-p-ala116 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown