Is IDH2 p.Pro23Ser (c.67C>T) pathogenic?

IDH2 p.Pro23Ser (c.67C>T) is classified Uncertain significance in IDH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-10). AlphaMissense: likely benign (0.073); Ultra-rare (popmax 0.0257%, mid); Associated with d-2-hydroxyglutaric aciduria 2.

What condition is associated with IDH2 p.Pro23Ser (c.67C>T)?

IDH2 p.Pro23Ser (c.67C>T) is associated with d-2-hydroxyglutaric aciduria 2 (ClinVar).

How common is IDH2 p.Pro23Ser (c.67C>T) in the general population?

IDH2 p.Pro23Ser (c.67C>T) is ultra-rare (popmax 0.0257%, mid) (gnomAD).

How is D-2-hydroxyglutaric aciduria inherited?

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

What do computational predictors say about IDH2 p.Pro23Ser (c.67C>T)?

AlphaMissense predicts likely benign (score 0.073) — an in-silico prediction, not a clinical call.

IDH2 p.Pro23Ser

c.67C>T · rs1433340280 · VCV1678685

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.073 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0257%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

d-2-hydroxyglutaric aciduria 2

Computational evidence

Protein change
AlphaMissense	0.073	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -7.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP -0.078, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 11 kb · p 0.027 · regional, not allelic
Overall
CADD	19.57	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0257% Middle Eastern · 1/3,890 alleles

Overall 0.000147% 2/1,361,788 alleles · ultra-rare exomes 2/1,210,724 · genomes 0/151,064 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0257%	3,890
East Asian	0.00322%	31,080

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.Pro23Ser
Coding: c.67C>T
MANE Select: NM_002168
dbSNP: rs1433340280
Type: single nucleotide variant
Location: chr15:90102324 (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.Pro23Arg Uncertain significance ★ ⚠ same residue
IDH2 p.Pro23= Likely benign ★ 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-pro23ser (accessed [today's date]).

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