Is MDH2 p.Val259Phe (c.775G>T) pathogenic?

MDH2 p.Val259Phe (c.775G>T) is classified Uncertain significance in MDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.9204); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with MDH2 p.Val259Phe (c.775G>T)?

MDH2 p.Val259Phe (c.775G>T) is associated with Inborn genetic diseases (ClinVar).

How common is MDH2 p.Val259Phe (c.775G>T) in the general population?

MDH2 p.Val259Phe (c.775G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MDH2 p.Val259Phe (c.775G>T)?

AlphaMissense predicts likely pathogenic (score 0.9204) — an in-silico prediction, not a clinical call.

MDH2 p.Val259Phe

c.775G>T · rs782161350 · VCV2560371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9204 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9204	likely pathogenic
REVEL	0.589	indeterminate
SaProt	LLR -12.67	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 18 kb · p 0.54 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,866 alleles

Overall 0.000124% 2/1,614,138 alleles · very rare exomes 2/1,461,850 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,866
European (non-Finnish)	8.47e-05%	1,180,032

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.Val259Phe
Coding: c.775G>T
MANE Select: NM_005918
dbSNP: rs782161350
Type: single nucleotide variant
Location: chr7:76064843 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.49 · 7 PDB
Residue 259: 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-val259phe (accessed [today's date]).

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