Is IDH2 p.Thr331= (c.993G>A) pathogenic?

IDH2 p.Thr331= (c.993G>A) is classified Benign/Likely benign in IDH2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-24). Low-frequency (popmax 4.25%, afr); Associated with d-2-hydroxyglutaric aciduria 2.

What condition is associated with IDH2 p.Thr331= (c.993G>A)?

IDH2 p.Thr331= (c.993G>A) is associated with d-2-hydroxyglutaric aciduria 2 (ClinVar).

How common is IDH2 p.Thr331= (c.993G>A) in the general population?

IDH2 p.Thr331= (c.993G>A) is low-frequency (popmax 4.25%, afr) (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.Thr331=

c.993G>A · rs61737002 · VCV158668

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.25%, afr)

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 -15	GERP -3.7
Overall
CADD	0.932	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.25% African / African-American · 3,128/73,602 alleles

Filtering AF 4.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.08%

Overall 0.227% 3,537/1,557,318 alleles · low-frequency exomes 1,707/1,405,054 · genomes 1,830/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.25%	24
Remaining individualsnot grpmax-eligible	0.315%	318
Admixed American	0.249%	402
Middle Eastern	0.133%	749
South Asian	0.026%	3,843
European (non-Finnish)	0.00531%	18,849

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.Thr331=
Coding: c.993G>A
MANE Select: NM_002168
dbSNP: rs61737002
Type: single nucleotide variant
Location: chr15:90085362 (GRCh38)
Gene constraint: LOEUF 0.502 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 92.07 · 13 PDB
Residue 331: a β-strand

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-thr331 (accessed [today's date]).

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