Is MTHFR p.Ala113= (c.339C>T) pathogenic?

MTHFR p.Ala113= (c.339C>T) is classified Likely benign in MTHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-26). Very rare (popmax 0.0011%, sas); Associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency.

What condition is associated with MTHFR p.Ala113= (c.339C>T)?

MTHFR p.Ala113= (c.339C>T) is associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

How common is MTHFR p.Ala113= (c.339C>T) in the general population?

MTHFR p.Ala113= (c.339C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

MTHFR p.Ala113=

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.339C>T · rs760081535 · VCV1930118

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 6.7	GERP 0.46, phastCons 1
Overall
CADD	12.39	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,084 alleles

Overall 6.84e-05% 1/1,461,886 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MTHFR
Protein: p.Ala113=
Coding: c.339C>T
MANE Select: NM_005957
dbSNP: rs760081535
Type: single nucleotide variant
Location: chr1:11801297 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 113: an α-helix; a UniProt-annotated variant site (in mthfrd; reduced methylenetetrahydrofolate reductase activity; no effect on affinity for nadph)

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.Ala113Thr Pathogenic/Likely pathogenic ★★ same residue
MTHFR p.Ala113Ser Likely pathogenic ★ ⚠ 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

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-ala113 (accessed [today's date]).

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