Is MDH2 p.Ala233= (c.699C>T) pathogenic?

MDH2 p.Ala233= (c.699C>T) is classified Likely benign in MDH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-21). Ultra-rare (popmax 0.0357%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MDH2 p.Ala233= (c.699C>T)?

MDH2 p.Ala233= (c.699C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MDH2 p.Ala233= (c.699C>T) in the general population?

MDH2 p.Ala233= (c.699C>T) is ultra-rare (popmax 0.0357%, nfe) (gnomAD).

MDH2 p.Ala233=

c.699C>T · rs149443188 · VCV1558750

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, nfe)

Conditions

Inborn genetic diseases

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 -9.4
Overall
CADD	8.071	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0357% European (non-Finnish) · 421/1,179,902 alleles

Filtering AF 0.0328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0317%

Overall 0.0283% 456/1,613,390 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0357%	2,803
Middle Eastern	0.0164%	6,080
Remaining individualsnot grpmax-eligible	0.016%	6,246
South Asian	0.011%	9,092
African / African-American	0.00935%	10,694
Admixed American	0.00667%	14,985
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,588
Finnishnot grpmax-eligible	0.00313%	31,947

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.Ala233=
Coding: c.699C>T
MANE Select: NM_005918
dbSNP: rs149443188
Type: single nucleotide variant
Location: chr7:76064404 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.49 · 7 PDB
Residue 233: 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-ala233 (accessed [today's date]).

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