Is MDH2 p.Pro99= (c.297G>A) pathogenic?

MDH2 p.Pro99= (c.297G>A) is classified Likely benign in MDH2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-01). Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with MDH2 p.Pro99= (c.297G>A)?

MDH2 p.Pro99= (c.297G>A) is associated with Inborn genetic diseases (ClinVar).

How common is MDH2 p.Pro99= (c.297G>A) in the general population?

MDH2 p.Pro99= (c.297G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

MDH2 p.Pro99=

c.297G>A · rs147689281 · VCV1013548

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

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 -5.2
Overall
CADD	0.565	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0118% 190/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
European (non-Finnish)	0.0142%	7,024
Admixed American	0.0133%	7,501
Remaining individualsnot grpmax-eligible	0.0112%	8,927
African / African-American	0.00668%	14,980

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.Pro99=
Coding: c.297G>A
MANE Select: NM_005918
dbSNP: rs147689281
Type: single nucleotide variant
Location: chr7:76057471 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.49 · 7 PDB

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.Pro99Leu Uncertain significance ★★ ⚠ same residue
MDH2 p.Pro99Gln Uncertain significance ★ ⚠ 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-pro99 (accessed [today's date]).

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