Is MDH2 p.Phe311Ser (c.932T>C) pathogenic?

MDH2 p.Phe311Ser (c.932T>C) is classified Uncertain significance in MDH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-29). AlphaMissense: ambiguous (0.3669); Very rare (popmax 0.00406%, afr); Associated with Inborn genetic diseases.

What condition is associated with MDH2 p.Phe311Ser (c.932T>C)?

MDH2 p.Phe311Ser (c.932T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MDH2 p.Phe311Ser (c.932T>C) in the general population?

MDH2 p.Phe311Ser (c.932T>C) is very rare (popmax 0.00406%, afr) (gnomAD).

What do computational predictors say about MDH2 p.Phe311Ser (c.932T>C)?

AlphaMissense predicts ambiguous (score 0.3669) — an in-silico prediction, not a clinical call.

MDH2 p.Phe311Ser

c.932T>C · rs782353063 · VCV1393849

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00406%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3669	ambiguous
REVEL	0.515	indeterminate
SaProt	LLR -10.83	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 18 kb · p 0.54 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00406% African / African-American · 3/73,864 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00273% 44/1,610,576 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00406%	24,621
European (non-Finnish)	0.00339%	29,475
East Asian	0.00223%	44,798

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: MDH2
Protein: p.Phe311Ser
Coding: c.932T>C
MANE Select: NM_005918
dbSNP: rs782353063
Type: single nucleotide variant
Location: chr7:76066325 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.49 · 7 PDB
Residue 311: an α-helix

Full MDH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MDH2 p.Ala135Gly Uncertain significance ★★ ⚠ same condition
MDH2 p.Ala141Thr Uncertain significance ★★ same condition
MDH2 p.Ala177Thr Uncertain significance ★★ ⚠ same condition
MDH2 p.Ala21Val Uncertain significance ★★ ⚠ same condition
MDH2 p.Ala242Val Uncertain significance ★★ ⚠ same condition
MDH2 p.Ala256Thr Uncertain significance ★★ ⚠ same condition
MDH2 p.Ala325Val Uncertain significance ★★ ⚠ same condition
MDH2 p.Ala66Thr Uncertain significance ★★ ⚠ 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/mdh2-p-phe311ser (accessed [today's date]).

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