D-2-hydroxyglutaric aciduria 2

Summary

D-2-hydroxyglutaric aciduria 2 (MONDO:0013345) is a disease caused by IDH2 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: IDH2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 199

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	d-2-hydroxyglutaric aciduria 2
Mondo ID	MONDO:0013345
OMIM	613657
DOID	DOID:0111352
UMLS	C3150909
MedGen	462259
GARD	0015685
Is cancer (heuristic)	no

Also known as: d-2-hydroxyglutaric aciduria 2 · D-2-hydroxyglutaric aciduria caused by mutation in IDH2 · D-2-hydroxyglutaric aciduria type 2 · D2HGA2 · IDH2 D-2-hydroxyglutaric aciduria

Data availability: 199 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › 2-hydroxyglutaric aciduria › D-2-hydroxyglutaric aciduria › d-2-hydroxyglutaric aciduria 2

Related subtypes (1): D-2-hydroxyglutaric aciduria 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

199 retrieved; paginated sample, class counts are floors:

97 uncertain significance, 70 likely benign, 12 benign, 9 benign/likely benign, 8 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14716	NM_002168.4(IDH2):c.419G>A (p.Arg140Gln)	IDH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14717	NM_002168.4(IDH2):c.418C>G (p.Arg140Gly)	IDH2	Pathogenic	no assertion criteria provided
828158	NM_002168.4(IDH2):c.1039G>A (p.Ala347Thr)	IDH2	Likely pathogenic	no assertion criteria provided
1347799	NM_002168.4(IDH2):c.1179-3T>A	IDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158664	NM_002168.4(IDH2):c.1304C>T (p.Thr435Met)	IDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158665	NM_002168.4(IDH2):c.327G>A (p.Val109=)	IDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211174	NM_002168.4(IDH2):c.1194G>A (p.Leu398=)	IDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211176	NM_002168.4(IDH2):c.673G>A (p.Asp225Asn)	IDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
452078	NM_002168.4(IDH2):c.1156G>C (p.Asp386His)	IDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
559362	NM_002168.4(IDH2):c.23T>C (p.Val8Ala)	IDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3243685	NC_000015.9:g.(?89379429)(91312836_?)del	ZNF774	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2422891	NC_000015.9:g.(?89379429)(91565479_?)dup	FURIN	Uncertain significance	criteria provided, single submitter
1010519	NM_002168.4(IDH2):c.1259A>T (p.His420Leu)	IDH2	Uncertain significance	criteria provided, single submitter
1030527	NM_002168.4(IDH2):c.373+5G>A	IDH2	Uncertain significance	criteria provided, single submitter
1030528	NM_002168.4(IDH2):c.877A>C (p.Met293Leu)	IDH2	Uncertain significance	criteria provided, single submitter
1042645	NM_002168.4(IDH2):c.1171C>T (p.Leu391Phe)	IDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1043109	NM_002168.4(IDH2):c.662T>C (p.Met221Thr)	IDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1054473	NM_002168.4(IDH2):c.967+2T>C	IDH2	Uncertain significance	criteria provided, single submitter
1064078	NM_002168.4(IDH2):c.320A>G (p.Tyr107Cys)	IDH2	Uncertain significance	criteria provided, single submitter
1336360	NM_002168.4(IDH2):c.62G>C (p.Trp21Ser)	IDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1371025	NM_002168.4(IDH2):c.389A>T (p.Lys130Met)	IDH2	Uncertain significance	criteria provided, single submitter
1380752	NM_002168.4(IDH2):c.534+2T>C	IDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1381906	NM_002168.4(IDH2):c.1081-3C>T	IDH2	Uncertain significance	criteria provided, single submitter
1382309	NM_002168.4(IDH2):c.223G>A (p.Val75Met)	IDH2	Uncertain significance	criteria provided, single submitter
1384307	NM_002168.4(IDH2):c.913G>A (p.Val305Met)	IDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1392576	NM_002168.4(IDH2):c.679-7C>A	IDH2	Uncertain significance	criteria provided, single submitter
1402900	NM_002168.4(IDH2):c.646G>A (p.Gly216Ser)	IDH2	Uncertain significance	criteria provided, single submitter
1406554	NM_002168.4(IDH2):c.1178G>A (p.Arg393Lys)	IDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1438194	NM_002168.4(IDH2):c.734C>T (p.Pro245Leu)	IDH2	Uncertain significance	criteria provided, single submitter
1490755	NM_002168.4(IDH2):c.1143C>G (p.His381Gln)	IDH2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
IDH2	Strong	Autosomal dominant	d-2-hydroxyglutaric aciduria 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IDH2	Orphanet:163634	Maffucci syndrome
IDH2	Orphanet:251589	Anaplastic astrocytoma
IDH2	Orphanet:251598	Protoplasmic astrocytoma
IDH2	Orphanet:251601	Fibrillary astrocytoma
IDH2	Orphanet:251604	Gemistocytic astrocytoma
IDH2	Orphanet:251627	Oligodendroglioma
IDH2	Orphanet:251630	Anaplastic oligodendroglioma
IDH2	Orphanet:251656	Oligoastrocytoma
IDH2	Orphanet:251663	Anaplastic oligoastrocytoma
IDH2	Orphanet:296	Ollier disease
IDH2	Orphanet:79315	D-2-hydroxyglutaric aciduria
IDH2	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IDH2	HGNC:5383	ENSG00000182054	P48735	Isocitrate dehydrogenase [NADP], mitochondrial	gencc,clinvar
ZNF774	HGNC:33108	ENSG00000196391	Q6NX45	Zinc finger protein 774	clinvar
FURIN	HGNC:8568	ENSG00000140564	P09958	Furin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IDH2	Isocitrate dehydrogenase [NADP], mitochondrial	Plays a role in intermediary metabolism and energy production.
ZNF774	Zinc finger protein 774	May be involved in transcriptional regulation.
FURIN	Furin	Ubiquitous endoprotease within constitutive secretory pathways capable of cleavage at the RX(K/R)R consensus motif.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	12.2×	0.239
Enzyme (other)	1	4.0×	0.321
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IDH2	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
ZNF774	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
FURIN	Protease	yes	3.4.21.75	Peptidase_S8/S53_dom, P_dom, Furin_repeat

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	2
apex of heart	1
hindlimb stylopod muscle	1
adrenal tissue	1
skeletal muscle tissue	1
body of pancreas	1
right lobe of liver	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IDH2	292	ubiquitous	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle
ZNF774	131	ubiquitous	marker	skeletal muscle tissue, gastrocnemius, adrenal tissue
FURIN	278	ubiquitous	marker	right lobe of liver, body of pancreas, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IDH2	4,912
FURIN	4,709
ZNF774	906

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FURIN	P09958	48
IDH2	P48735	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZNF774	Q6NX45	73.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis and processing of ENV and VPU	1	3806.7×	0.008	FURIN
NGF processing	1	951.7×	0.012	FURIN
Assembly and Release of Dengue Virus Virions	1	475.8×	0.012	FURIN
Removal of aminoterminal propeptides from gamma-carboxylated proteins	1	380.7×	0.012	FURIN
CD163 mediating an anti-inflammatory response	1	380.7×	0.012	FURIN
GBP-mediated host defense	1	346.1×	0.012	FURIN
Uptake and function of anthrax toxins	1	317.2×	0.012	FURIN
Induction of Cell-Cell Fusion	1	292.8×	0.012	FURIN
Maturation of hRSV A proteins	1	253.8×	0.012	FURIN
Pre-NOTCH Processing in Golgi	1	211.5×	0.012	FURIN
Assembly of active LPL and LIPC lipase complexes	1	200.3×	0.012	FURIN
Attachment and Entry	1	200.3×	0.012	FURIN
Maturation of TCA enzymes and regulation of TCA cycle	1	190.3×	0.012	IDH2
Signaling by NODAL	1	165.5×	0.012	FURIN
Respiratory syncytial virus (RSV) attachment and entry	1	165.5×	0.012	FURIN
Citric acid cycle (TCA cycle)	1	141.0×	0.013	IDH2
Elastic fibre formation	1	112.0×	0.014	FURIN
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	112.0×	0.014	FURIN
TGF-beta receptor signaling activates SMADs	1	108.8×	0.014	FURIN
Activation of Matrix Metalloproteinases	1	102.9×	0.014	FURIN
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	102.9×	0.014	FURIN
Dengue Virus Attachment and Entry	1	86.5×	0.015	FURIN
Signaling by PDGF	1	84.6×	0.015	FURIN
Transcriptional activation of mitochondrial biogenesis	1	68.0×	0.018	IDH2
Collagen degradation	1	58.6×	0.020	FURIN
Potential therapeutics for SARS	1	38.1×	0.029	FURIN
Mitochondrial protein degradation	1	38.1×	0.029	IDH2
Amyloid fiber formation	1	34.3×	0.031	FURIN
Formation of the cornified envelope	1	29.3×	0.035	FURIN
Generic Transcription Pathway	1	5.0×	0.186	ZNF774

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dibasic protein processing	1	5617.3×	0.003	FURIN
glyoxylate cycle	1	2808.7×	0.003	IDH2
nerve growth factor production	1	2808.7×	0.003	FURIN
negative regulation of glial cell migration	1	2808.7×	0.003	IDH2
negative regulation of matrix metallopeptidase secretion	1	2808.7×	0.003	IDH2
negative regulation of low-density lipoprotein particle receptor catabolic process	1	1872.4×	0.003	FURIN
viral life cycle	1	1404.3×	0.003	FURIN
plasma lipoprotein particle remodeling	1	1404.3×	0.003	FURIN
peptide biosynthetic process	1	1404.3×	0.003	FURIN
isocitrate metabolic process	1	1123.5×	0.003	IDH2
cytokine precursor processing	1	1123.5×	0.003	FURIN
negative regulation of transforming growth factor beta1 production	1	936.2×	0.003	FURIN
NADP+ biosynthetic process	1	802.5×	0.003	IDH2
regulation of cholesterol transport	1	802.5×	0.003	FURIN
secretion by cell	1	561.7×	0.004	FURIN
negative regulation of glial cell proliferation	1	561.7×	0.004	IDH2
NADP+ metabolic process	1	510.7×	0.004	IDH2
obsolete signal peptide processing	1	468.1×	0.005	FURIN
positive regulation of viral entry into host cell	1	401.2×	0.005	FURIN
2-oxoglutarate metabolic process	1	312.1×	0.006	IDH2
peptide hormone processing	1	312.1×	0.006	FURIN
positive regulation of membrane protein ectodomain proteolysis	1	312.1×	0.006	FURIN
regulation of protein catabolic process	1	280.9×	0.006	FURIN
blastocyst formation	1	255.3×	0.006	FURIN
zymogen activation	1	224.7×	0.007	FURIN
negative regulation of inflammatory response to antigenic stimulus	1	200.6×	0.007	FURIN
amyloid fibril formation	1	200.6×	0.007	FURIN
viral protein processing	1	181.2×	0.008	FURIN
tricarboxylic acid cycle	1	170.2×	0.008	IDH2
collagen catabolic process	1	130.6×	0.010	FURIN

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
IDH2	ENASIDENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IDH2	7	4
FURIN	1	2
ZNF774	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENASIDENIB	4	IDH2
ENASIDENIB MESYLATE	4	IDH2
IVOSIDENIB	4	IDH2
VORASIDENIB	4	IDH2
OLUTASIDENIB	4	IDH2
CRELOSIDENIB	2	IDH2
RANOSIDENIB	2	IDH2
DIMINAZENE	2	FURIN

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
IDH2	84	Binding:84
FURIN	62	Binding:62

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IDH2	1.1.1.42	isocitrate dehydrogenase (NADP+)
FURIN	3.4.21.75	Furin

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

8 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ENASIDENIB	4	IDH2
ENASIDENIB MESYLATE	4	IDH2
IVOSIDENIB	4	IDH2
VORASIDENIB	4	IDH2
OLUTASIDENIB	4	IDH2
CRELOSIDENIB	2	IDH2
RANOSIDENIB	2	IDH2
DIMINAZENE	2	FURIN

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	IDH2
B	Phased (≥1) drug, not yet approved	1	FURIN
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ZNF774

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ZNF774	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.