IDH2

Chr 15

isocitrate dehydrogenase (NADP(+)) 2

Also known as: D2HGA2, ICD-M, IDH, IDH-2, IDHM, IDP, IDPM, mNADP-IDH

NCBI Gene: 3418 ENSG00000182054 UniProt: P48735 OMIM: 147650

The protein is a mitochondrial NADP(+)-dependent isocitrate dehydrogenase that catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate in intermediary metabolism and energy production. Mutations cause D-2-hydroxyglutaric aciduria 2, a metabolic disorder with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variation (pLI 0.88, LOEUF 0.38), indicating that functional copies are critical for normal cellular metabolism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

OMIM ResearchGenerating clinical summary…

LOEUF 0.381 OMIM phenotype

Clinical Summary— IDH2

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.88) — some intolerance to loss-of-function variants.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 152 VUS of 290 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.38LOEUF

pLI 0.883

Z-score 3.54

OE 0.15 (0.07–0.38)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.34Z-score

OE missense 0.76 (0.68–0.86)

191 obs / 250.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.07–0.38)

0≤0.351.4

Missense OE?0.76 (0.68–0.86)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 3 / 20.2Missense obs/exp: 191 / 250.8Syn Z: -2.17

ClinVar Variant Classifications

290 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic4

VUS152

Likely Benign87

Benign31

Conflicting8

Pathogenic

Likely Pathogenic

152

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	0	4	0	0	4
VUS	9	128	13	2	152
Likely Benign	0	5	29	53	87
Benign	0	0	24	7	31
Conflicting	—				8
Total	9	139	66	62	284

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

41 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap IDH2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

IDH2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING

NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21

NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies

Recurrent Malignant GliomaGlioblastomaAnaplastic Astrocytoma

Comprehensive Analysis of Chemotherapy and Targeted Therapy Outcomes in Recurrent Malignant Gliomas

ACTIVE NOT RECRUITING

NCT07448480Blokhin's Russian Cancer Research CenterStarted 2026-02-01

Bevacizumab-Containing RegimensNon-Bevacizumab RegimensBRAF ± MEK Targeted Therapy

Acute Bilineal LeukemiaAcute Biphenotypic LeukemiaChronic Myelomonocytic Leukemia

Enasidenib and Azacitidine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia and IDH2 Gene Mutation

RECRUITING

NCT03683433Phase PHASE2M.D. Anderson Cancer CenterStarted 2018-09-18

AzacitidineEnasidenib Mesylate

Acute Myeloid Leukemia

IDH Targeted/Non- Targeted vs Non-targeted/IDH-targeted Approaches in the Treatment of Newly Diagnosed IDH Mutated AML Patients Not Candidates for Intensive Induction Therapy (I- DATA Study)

RECRUITING

NCT05401097Phase PHASE2Alice MimsStarted 2022-09-13

AzacitidineBiopsyEnasidenib

GliomaGlioblastomaHigh Grade Glioma

Nivolumab in Patients With IDH-Mutant Gliomas With and Without Hypermutator Phenotype

ACTIVE NOT RECRUITING

NCT03718767Phase PHASE2National Cancer Institute (NCI)Started 2019-03-27

Nivolumab

AMLIDH1 MutationTreatment

Venetoclax in Combination With Ivosidenib and Azacitidine for Newly Diagnosed IDH1-Mutated AML

RECRUITING

NCT06611839Phase PHASE1, PHASE2Institute of Hematology & Blood Diseases Hospital, ChinaStarted 2025-10-17