Is MDH2 p.Val95Ala (c.284T>C) pathogenic?

MDH2 p.Val95Ala (c.284T>C) is classified Uncertain significance in MDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-25). AlphaMissense: likely pathogenic (0.7108); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MDH2 p.Val95Ala (c.284T>C)?

MDH2 p.Val95Ala (c.284T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MDH2 p.Val95Ala (c.284T>C) in the general population?

MDH2 p.Val95Ala (c.284T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MDH2 p.Val95Ala (c.284T>C)?

AlphaMissense predicts likely pathogenic (score 0.7108) — an in-silico prediction, not a clinical call.

MDH2 p.Val95Ala

c.284T>C · rs2535857910 · VCV2561517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7108 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7108	likely pathogenic
REVEL	0.659	pathogenic-leaning
SaProt	LLR -7.73	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.26 · evaluated, not missing
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	24.2	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

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: MDH2
Protein: p.Val95Ala
Coding: c.284T>C
MANE Select: NM_005918
dbSNP: rs2535857910
Type: single nucleotide variant
Location: chr7:76057458 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.49 · 7 PDB
Residue 95: a β-strand

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.Val95Gly Uncertain significance ★ ⚠ same residue
MDH2 p.Val95= Likely benign ★ same residue
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

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-val95ala (accessed [today's date]).

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