Is IDH2 p.Val7= (c.21C>T) pathogenic?

IDH2 p.Val7= (c.21C>T) is classified Likely benign in IDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). Ultra-rare (popmax 0.0134%, nfe); Associated with d-2-hydroxyglutaric aciduria 2.

What condition is associated with IDH2 p.Val7= (c.21C>T)?

IDH2 p.Val7= (c.21C>T) is associated with d-2-hydroxyglutaric aciduria 2 (ClinVar).

How common is IDH2 p.Val7= (c.21C>T) in the general population?

IDH2 p.Val7= (c.21C>T) is ultra-rare (popmax 0.0134%, nfe) (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.Val7=

c.21C>T · rs768052048 · VCV2158232

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, nfe)

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 0.61	GERP -1.2, phastCons 0.098
Overall
CADD	11.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% European (non-Finnish) · 140/1,047,578 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.0103% 141/1,363,036 alleles · ultra-rare exomes 137/1,211,832 · genomes 4/151,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0134%	7,483
Remaining individualsnot grpmax-eligible	0.002%	50,116

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.Val7=
Coding: c.21C>T
MANE Select: NM_002168
dbSNP: rs768052048
Type: single nucleotide variant
Location: chr15:90102370 (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.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
IDH2 p.Arg60His Uncertain significance ★★ ⚠ same condition
IDH2 p.Asp439Asn 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-val7 (accessed [today's date]).

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