Is IDH2 p.Ala40= (c.120C>T) pathogenic?

IDH2 p.Ala40= (c.120C>T) is classified Likely benign in IDH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-17). Ultra-rare (popmax 0.049%, eas); Associated with d-2-hydroxyglutaric aciduria 2.

What condition is associated with IDH2 p.Ala40= (c.120C>T)?

IDH2 p.Ala40= (c.120C>T) is associated with d-2-hydroxyglutaric aciduria 2 (ClinVar).

How common is IDH2 p.Ala40= (c.120C>T) in the general population?

IDH2 p.Ala40= (c.120C>T) is ultra-rare (popmax 0.049%, 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.Ala40=

c.120C>T · rs148974231 · VCV715534

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.049%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -2.7
Overall
CADD	6.436	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.049% East Asian · 22/44,894 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0279%

Overall 0.0062% 100/1,613,752 alleles · ultra-rare exomes 79/1,461,568 · genomes 21/152,184 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.049%	2,041
Admixed American	0.0233%	4,287
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0064%	15,619
South Asian	0.00549%	18,217
European (non-Finnish)	0.00432%	23,132
African / African-American	0.00401%	24,965

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.Ala40=
Coding: c.120C>T
MANE Select: NM_002168
dbSNP: rs148974231
Type: single nucleotide variant
Location: chr15:90091640 (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-ala40 (accessed [today's date]).

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