Is MDH2 p.Phe333= (c.999C>T) pathogenic?

MDH2 p.Phe333= (c.999C>T) is classified Benign/Likely benign in MDH2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). Rare (popmax 0.265%, afr); Associated with Inborn genetic diseases.

What condition is associated with MDH2 p.Phe333= (c.999C>T)?

MDH2 p.Phe333= (c.999C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MDH2 p.Phe333= (c.999C>T) in the general population?

MDH2 p.Phe333= (c.999C>T) is rare (popmax 0.265%, afr) (gnomAD).

MDH2 p.Phe333=

c.999C>T · rs146761624 · VCV724398

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.265%, afr)

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 -2.4
Overall
CADD	7.272	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.265% African / African-American · 197/74,340 alleles

Filtering AF 0.235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.223%

Overall 0.0363% 585/1,611,642 alleles · rare exomes 441/1,461,242 · genomes 144/150,400 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.265%	377
Middle Eastern	0.198%	504
Admixed American	0.107%	931
Remaining individualsnot grpmax-eligible	0.0785%	1,274
European (non-Finnish)	0.022%	4,553
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,859
South Asian	0.0011%	90,810

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.Phe333=
Coding: c.999C>T
MANE Select: NM_005918
dbSNP: rs146761624
Type: single nucleotide variant
Location: chr7:76066392 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.49 · 7 PDB
Residue 333: 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-phe333 (accessed [today's date]).

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