Is IDH2 p.Pro337= (c.1011T>G) pathogenic?

IDH2 p.Pro337= (c.1011T>G) is classified Likely benign in IDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-03). Ultra-rare (popmax 0.0288%, eas); Associated with d-2-hydroxyglutaric aciduria 2.

What condition is associated with IDH2 p.Pro337= (c.1011T>G)?

IDH2 p.Pro337= (c.1011T>G) is associated with d-2-hydroxyglutaric aciduria 2 (ClinVar).

How common is IDH2 p.Pro337= (c.1011T>G) in the general population?

IDH2 p.Pro337= (c.1011T>G) is ultra-rare (popmax 0.0288%, eas) (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.Pro337=

c.1011T>G · rs1222450557 · VCV1541594

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0288%, eas)

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	<0.2	all four deltas below 0.2 · A>T here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP -15	GERP -3.4
Overall
CADD	0.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0288% East Asian · 12/41,680 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.000771% 12/1,555,908 alleles · ultra-rare exomes 9/1,403,818 · genomes 3/152,090 · joint denominator

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.Pro337=
Coding: c.1011T>G
MANE Select: NM_002168
dbSNP: rs1222450557
Type: single nucleotide variant
Location: chr15:90085344 (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.Pro337Leu 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
IDH2 p.Arg60His 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-pro337 (accessed [today's date]).

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