Is IDH2 p.Pro23= (c.69G>C) pathogenic?

IDH2 p.Pro23= (c.69G>C) is classified Likely benign in IDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-15). Very rare (popmax 0.00527%, amr); Associated with d-2-hydroxyglutaric aciduria 2.

What condition is associated with IDH2 p.Pro23= (c.69G>C)?

IDH2 p.Pro23= (c.69G>C) is associated with d-2-hydroxyglutaric aciduria 2 (ClinVar).

How common is IDH2 p.Pro23= (c.69G>C) in the general population?

IDH2 p.Pro23= (c.69G>C) is very rare (popmax 0.00527%, amr) (gnomAD).

How is D-2-hydroxyglutaric aciduria inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

IDH2 p.Pro23=

c.69G>C · rs1232539137 · VCV2178189

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00527%, amr)

Conditions

d-2-hydroxyglutaric aciduria 2

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 -7.5	GERP -2.1
Overall
CADD	7.814	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00527% Admixed American · 2/37,972 alleles

Filtering AF 0.000873% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000326%

Overall 0.000221% 3/1,357,808 alleles · very rare exomes 3/1,206,658 · genomes 0/151,150 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00527%	18,986
European (non-Finnish)	9.57e-05%	1,044,876

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: IDH2
Protein: p.Pro23=
Coding: c.69G>C
MANE Select: NM_002168
dbSNP: rs1232539137
Type: single nucleotide variant
Location: chr15:90102322 (GRCh38)
Gene constraint: LOEUF 0.502 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 92.07 · 13 PDB

Full IDH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

d-2-hydroxyglutaric aciduria 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For D-2-hydroxyglutaric aciduria (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

IDH2 p.Pro23Ser Uncertain significance ★★ ⚠ same residue
IDH2 p.Pro23Arg Uncertain significance ★ ⚠ same residue
IDH2 p.Arg140Gln Pathogenic/Likely pathogenic ★★ same condition
IDH2 c.1271+3G>A Uncertain significance ★★ same condition
IDH2 c.534+2T>C Uncertain significance ★★ same condition
IDH2 p.Ala214Thr Uncertain significance ★★ ⚠ same condition
IDH2 p.Arg362Trp Uncertain significance ★★ ⚠ same condition
IDH2 p.Arg393Lys 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/idh2-p-pro23 (accessed [today's date]).

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