Maffucci syndrome

Summary

Maffucci syndrome (MONDO:0013808) is a disease with 7 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 7
• ClinVar variants: 14
• Phenotypes (HPO): 24
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		250	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0002797	Osteolysis	Very frequent (80-99%)
HP:0004936	Venous thrombosis	Very frequent (80-99%)
HP:0005701	Multiple enchondromatosis	Very frequent (80-99%)
HP:0007461	Hemangiomatosis	Very frequent (80-99%)
HP:0001482	Subcutaneous nodule	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002653	Bone pain	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0100777	Exostoses	Frequent (30-79%)
HP:0000853	Goiter	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002757	Recurrent fractures	Occasional (5-29%)
HP:0002893	Pituitary adenoma	Occasional (5-29%)
HP:0002897	Parathyroid adenoma	Occasional (5-29%)
HP:0003002	Breast carcinoma	Occasional (5-29%)
HP:0006765	Chondrosarcoma	Occasional (5-29%)
HP:0006824	Cranial nerve paralysis	Occasional (5-29%)
HP:0009592	Astrocytoma	Occasional (5-29%)
HP:0100021	Cerebral palsy	Occasional (5-29%)
HP:0100242	Sarcoma	Occasional (5-29%)
HP:0100615	Ovarian neoplasm	Occasional (5-29%)
HP:0100641	Neoplasm of the adrenal cortex	Occasional (5-29%)
HP:0100733	Neoplasm of the parathyroid gland	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Maffucci syndrome
Mondo ID	MONDO:0013808
OMIM	614569
Orphanet	163634
DOID	DOID:0060221
ICD-11	548780091
NCIT	C3213
SNOMED CT	46041001
UMLS	C0024454
MedGen	7437
GARD	0006958
NORD	1393
Is cancer (heuristic)	no

Also known as: chondrodysplasia with hemangioma · Chondroplasia angiomatosis · Dyschondrodysplasia with hemangiomas · Dyschondroplasia and cavernous hemangioma · enchondromatosis with hemangiomata · enchondromatosis with multiple cavernous hemangiomas · hemangiomata with Dyschondroplasia · hemangiomatosis Chondrodystrophica · Kast syndrome · Maffucci syndrome · Maffucci type enchondromatosis · Maffucci’s anomalad · multiple Angiomas and Endochondromas

Data availability: 14 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › skin neoplasm › Maffucci syndrome

Related subtypes (16): dermoid cyst of skin, eyelid neoplasm, epidermal appendage tumor, dermis tumor, skin cancer, benign dermal neurilemmoma, actinic keratosis, familial Dupuytren contracture, schwannomatosis, familial multiple discoid fibromas, hemangiopericytoma of skin, benign neoplasm of skin, melanocytic skin neoplasm, epithelial skin neoplasm, calcifying epithelial odontogenic tumor, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome

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

14 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 4 likely pathogenic, 3 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
375891	NM_005896.4(IDH1):c.394C>T (p.Arg132Cys)	IDH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679886	NM_001844.5(COL2A1):c.1955A>G (p.Glu652Gly)	COL2A1	Likely pathogenic	criteria provided, single submitter
1803803	NM_001530.4(HIF1A):c.1961C>T (p.Ala654Val)	HIF1A	Likely pathogenic	criteria provided, single submitter
1803805	NM_001530.4(HIF1A):c.1369G>A (p.Glu457Lys)	HIF1A	Likely pathogenic	criteria provided, single submitter
376439	NM_002168.4(IDH2):c.514A>G (p.Arg172Gly)	IDH2	Likely pathogenic	criteria provided, single submitter
135826	NM_000077.5(CDKN2A):c.318G>A (p.Val106=)	CDKN2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803796	NM_001530.4(HIF1A):c.148G>C (p.Val50Leu)	HIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220627	NM_000551.4(VHL):c.628C>T (p.Arg210Trp)	LOC107303340	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803801	NM_000077.5(CDKN2A):c.50C>G (p.Ala17Gly)	CDKN2A	Uncertain significance	criteria provided, single submitter
3238635	NM_005896.4(IDH1):c.943C>T (p.His315Tyr)	IDH1	Uncertain significance	criteria provided, single submitter
4279963	NM_005896.4(IDH1):c.580C>T (p.His194Tyr)	IDH1	Uncertain significance	criteria provided, single submitter
4279964	NM_005896.4(IDH1):c.297A>G (p.Ile99Met)	IDH1	Uncertain significance	criteria provided, single submitter
1803799	NM_015061.6(KDM4C):c.1112G>A (p.Arg371Gln)	KDM4C	Uncertain significance	criteria provided, single submitter
93330	NM_000551.4(VHL):c.74C>T (p.Pro25Leu)	VHL	Benign	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 48 · 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
IDH1	Limited	Autosomal dominant	Maffucci syndrome

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IDH1	Orphanet:163634	Maffucci syndrome
IDH1	Orphanet:251576	Gliosarcoma
IDH1	Orphanet:251579	Giant cell glioblastoma
IDH1	Orphanet:296	Ollier disease
IDH1	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
IDH1	Orphanet:99646	Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria
VHL	Orphanet:238557	Chuvash erythrocytosis
VHL	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
VHL	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
VHL	Orphanet:892	Von Hippel-Lindau disease
CDKN2A	Orphanet:1333	Familial pancreatic carcinoma
CDKN2A	Orphanet:1501	Adrenocortical carcinoma
CDKN2A	Orphanet:252206	Melanoma and neural system tumor syndrome
CDKN2A	Orphanet:404560	Familial atypical multiple mole melanoma syndrome
CDKN2A	Orphanet:524	Li-Fraumeni syndrome
CDKN2A	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
CDKN2A	Orphanet:618	Familial melanoma
CDKN2A	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
COL2A1	Orphanet:137678	Spondyloepiphyseal dysplasia with metatarsal shortening
COL2A1	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL2A1	Orphanet:1856	Spondyloperipheral dysplasia-short ulna syndrome
COL2A1	Orphanet:209867	Autosomal dominant rhegmatogenous retinal detachment
COL2A1	Orphanet:2380	Legg-Calvé-Perthes disease
COL2A1	Orphanet:459051	Spondyloepiphyseal dysplasia, Stanescu type
COL2A1	Orphanet:485	Kniest dysplasia
COL2A1	Orphanet:85166	Platyspondylic dysplasia, Torrance type
COL2A1	Orphanet:85198	Dysspondyloenchondromatosis
COL2A1	Orphanet:86820	Familial avascular necrosis of femoral head
COL2A1	Orphanet:90653	Stickler syndrome type 1
COL2A1	Orphanet:93279	Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
COL2A1	Orphanet:93296	Achondrogenesis type 2
COL2A1	Orphanet:93297	Hypochondrogenesis
COL2A1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type
COL2A1	Orphanet:93316	Spondylometaphyseal dysplasia, Schmidt type
COL2A1	Orphanet:93346	Spondyloepimetaphyseal dysplasia congenita, Strudwick type
COL2A1	Orphanet:94068	Spondyloepiphyseal dysplasia congenita
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

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IDH1	HGNC:5382	ENSG00000138413	O75874	Isocitrate dehydrogenase [NADP] cytoplasmic	gencc,clinvar
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	clinvar
KDM4C	HGNC:17071	ENSG00000107077	Q9H3R0	Lysine-specific demethylase 4C	clinvar
CDKN2A	HGNC:1787	ENSG00000147889	P42771	Cyclin-dependent kinase inhibitor 2A	clinvar
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	clinvar
HIF1A	HGNC:4910	ENSG00000100644	Q16665	Hypoxia-inducible factor 1-alpha	clinvar
IDH2	HGNC:5383	ENSG00000182054	P48735	Isocitrate dehydrogenase [NADP], mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IDH1	Isocitrate dehydrogenase [NADP] cytoplasmic	Catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (D-threo-isocitrate) to 2-ketoglutarate (2-oxoglutarate), which is required by other enzymes such as the phytanoyl-CoA dioxygenase.
VHL	von Hippel-Lindau disease tumor suppressor	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
KDM4C	Lysine-specific demethylase 4C	Histone demethylase that specifically demethylates ‘Lys-9’ and ‘Lys-36’ residues of histone H3, thereby playing a central role in histone code.
CDKN2A	Cyclin-dependent kinase inhibitor 2A	Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6.
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.
HIF1A	Hypoxia-inducible factor 1-alpha	Functions as a master transcriptional regulator of the adaptive response to hypoxia.
IDH2	Isocitrate dehydrogenase [NADP], mitochondrial	Plays a role in intermediary metabolism and energy production.

Protein-family classification

Druggable: 3 · Difficult: 3 · Unknown: 1 · Druggable fraction: 0.43

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
Enzyme (other)	3	5.1×	0.063
Transcription factor	2	2.4×	0.408
Scaffold/PPI	1	2.5×	0.455
Other/Unknown	1	0.3×	0.997

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IDH1	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
VHL	Enzyme (other)	yes	2.3.2.B13	VHL_tumour_suppress_b/a_dom, VHL_alpha_dom, VHL_beta_dom
KDM4C	Transcription factor	no	1.14.11.27	Znf_PHD, Tudor, JmjC_dom
CDKN2A	Scaffold/PPI	no		Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor, Tumor_suppres_ARF
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
HIF1A	Transcription factor	no		PAS, HIF-1_alpha, PAC
IDH2	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus epididymis	3
adrenal tissue	1
jejunal mucosa	1
cortical plate	1
monocyte	1
mononuclear cell	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
cervix squamous epithelium	1
parotid gland	1
pituitary gland	1
cartilage tissue	1
tibia	1
epithelial cell of pancreas	1
pancreatic ductal cell	1
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IDH1	294	ubiquitous	marker	corpus epididymis, jejunal mucosa, adrenal tissue
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
KDM4C	250	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CDKN2A	220	ubiquitous	marker	parotid gland, cervix squamous epithelium, pituitary gland
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis
HIF1A	295	ubiquitous	marker	pancreatic ductal cell, epithelial cell of pancreas, corpus epididymis
IDH2	292	ubiquitous	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HIF1A	9,734
CDKN2A	9,311
IDH1	5,464
IDH2	4,912
VHL	3,522
COL2A1	2,491
KDM4C	1,380

Intra-cohort edges

A	B	Sources
CDKN2A	HIF1A	string_interaction
HIF1A	KDM4C	biogrid_interaction, string_interaction
HIF1A	VHL	biogrid_interaction, intact, string_interaction
IDH1	IDH2	biogrid_interaction

Structural data

PDB: 7 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VHL	P40337	142
IDH1	O75874	61
HIF1A	Q16665	25
COL2A1	P02458	11
IDH2	P48735	11
KDM4C	Q9H3R0	7
CDKN2A	P42771	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 105. Enrichment computed across 7 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate	1	1631.4×	0.013	IDH1
Evasion of Oncogene Induced Senescence Due to p14ARF Defects	1	1631.4×	0.013	CDKN2A
Evasion of Oxidative Stress Induced Senescence Due to p14ARF Defects	1	1631.4×	0.013	CDKN2A
NADPH regeneration	1	815.7×	0.013	IDH1
Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4	1	815.7×	0.013	CDKN2A
Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4	1	815.7×	0.013	CDKN2A
Defective Intrinsic Pathway for Apoptosis Due to p14ARF Loss of Function	1	815.7×	0.013	CDKN2A
Diseases of Cellular Senescence	1	543.8×	0.013	CDKN2A
Evasion of Oncogene Induced Senescence Due to p16INK4A Defects	1	543.8×	0.013	CDKN2A
Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6	1	543.8×	0.013	CDKN2A
Evasion of Oxidative Stress Induced Senescence Due to p16INK4A Defects	1	543.8×	0.013	CDKN2A
Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6	1	543.8×	0.013	CDKN2A
Diseases of cellular response to stress	1	543.8×	0.013	CDKN2A
NFE2L2 regulating TCA cycle genes	1	543.8×	0.013	IDH1
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	2	56.3×	0.013	VHL, HIF1A
Replication of the SARS-CoV-1 genome	1	407.9×	0.015	VHL
Replication of the SARS-CoV-2 genome	1	407.9×	0.015	VHL
PTK6 Expression	1	271.9×	0.021	HIF1A
PTK6 promotes HIF1A stabilization	1	233.1×	0.024	HIF1A
RUNX3 regulates p14-ARF	1	163.1×	0.031	CDKN2A
RHOBTB3 ATPase cycle	1	163.1×	0.031	VHL
STAT3 nuclear events downstream of ALK signaling	1	148.3×	0.032	HIF1A
Regulation of gene expression by Hypoxia-inducible Factor	1	135.9×	0.033	HIF1A
Apoptotic factor-mediated response	1	125.5×	0.033	CDKN2A
Cellular response to hypoxia	1	125.5×	0.033	HIF1A
Stabilization of p53	1	108.8×	0.034	CDKN2A
Defective Intrinsic Pathway for Apoptosis	1	108.8×	0.034	CDKN2A
p53-Dependent G1 DNA Damage Response	1	102.0×	0.034	CDKN2A
p53-Dependent G1/S DNA damage checkpoint	1	102.0×	0.034	CDKN2A
Neddylation	2	13.5×	0.034	VHL, HIF1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glyoxylate cycle	2	2407.4×	3e-05	IDH1, IDH2
regulation of gene expression	4	47.7×	7e-05	VHL, KDM4C, COL2A1, HIF1A
isocitrate metabolic process	2	963.0×	9e-05	IDH1, IDH2
NADP+ metabolic process	2	437.7×	4e-04	IDH1, IDH2
2-oxoglutarate metabolic process	2	267.5×	9e-04	IDH1, IDH2
amyloid fibril formation	2	172.0×	0.002	VHL, CDKN2A
tricarboxylic acid cycle	2	145.9×	0.002	IDH1, IDH2
chondrocyte differentiation	2	86.0×	0.005	COL2A1, HIF1A
regulation of phospholipid catabolic process	1	2407.4×	0.009	IDH1
nuclear body organization	1	1203.7×	0.011	CDKN2A
elastin metabolic process	1	1203.7×	0.011	HIF1A
positive regulation of chemokine-mediated signaling pathway	1	1203.7×	0.011	HIF1A
regulation of phospholipid biosynthetic process	1	1203.7×	0.011	IDH1
negative regulation of glial cell migration	1	1203.7×	0.011	IDH2
negative regulation of matrix metallopeptidase secretion	1	1203.7×	0.011	IDH2
neural fold elevation formation	1	802.5×	0.011	HIF1A
positive regulation of hormone biosynthetic process	1	802.5×	0.011	HIF1A
apoptotic process involved in mammary gland involution	1	802.5×	0.011	CDKN2A
obsolete positive regulation of nitric oxide metabolic process	1	802.5×	0.011	HIF1A
positive regulation of macrophage apoptotic process	1	802.5×	0.011	CDKN2A
B-1 B cell homeostasis	1	601.9×	0.011	HIF1A
regulation of transforming growth factor beta2 production	1	601.9×	0.011	HIF1A
positive regulation of apoptotic process involved in mammary gland involution	1	601.9×	0.011	CDKN2A
intestinal epithelial cell maturation	1	601.9×	0.011	HIF1A
epithelial cell differentiation involved in mammary gland alveolus development	1	601.9×	0.011	HIF1A
hypoxia-inducible factor-1alpha signaling pathway	1	601.9×	0.011	HIF1A
obsolete negative regulation of proteolysis involved in protein catabolic process	1	601.9×	0.011	CDKN2A
cellular response to hypoxia	2	34.6×	0.011	VHL, HIF1A
positive regulation of DNA-templated transcription	3	12.0×	0.011	VHL, CDKN2A, HIF1A
NADPH regeneration	1	481.5×	0.012	IDH1

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 5 · Phased (≥1): 5 · Undrugged: 2

Druggability breadth: 7 of 7 evidence-associated genes (100%) 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
IDH1	ENASIDENIB
VHL	OSIMERTINIB
HIF1A	EMETINE
IDH2	ENASIDENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HIF1A	255	4
IDH1	10	4
VHL	7	4
IDH2	7	4
KDM4C	4	3
CDKN2A	0	0
COL2A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENASIDENIB	4	IDH1, IDH2
IVOSIDENIB	4	IDH1, IDH2
VORASIDENIB	4	IDH1, IDH2
OLUTASIDENIB	4	IDH1, IDH2
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
ADAGRASIB	4	VHL
EMETINE	4	HIF1A
DOXORUBICIN	4	HIF1A
TOPOTECAN	4	HIF1A
LEVOSALBUTAMOL	4	HIF1A
LEVODOPA	4	HIF1A
DIENESTROL	4	HIF1A
PROGESTERONE	4	HIF1A
DICLOFENAC SODIUM	4	HIF1A
CLOTRIMAZOLE	4	HIF1A
BUMETANIDE	4	HIF1A
MORICIZINE	4	HIF1A
HYDROCORTISONE ACETATE	4	HIF1A
CHLORMADINONE ACETATE	4	HIF1A
DROPERIDOL	4	HIF1A
AMOXAPINE	4	HIF1A
TORSEMIDE	4	HIF1A
PREDNISOLONE ACETATE	4	HIF1A
BENOXINATE	4	HIF1A
NICARDIPINE HYDROCHLORIDE	4	HIF1A
PHENYLEPHRINE HYDROCHLORIDE	4	HIF1A
SULCONAZOLE NITRATE	4	HIF1A
HYDROXYZINE PAMOATE	4	HIF1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39
IDH1	488	Binding:475, Functional:12, ADMET:1
HIF1A	427	Binding:411, Functional:16
KDM4C	122	Binding:120, Functional:2
IDH2	84	Binding:84
CDKN2A	2	Binding:2
COL2A1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IDH1	1.1.1.42	isocitrate dehydrogenase (NADP+)
VHL	2.3.2.B13
KDM4C	1.14.11.27, 1.14.11.66, 1.14.11.69	[histone H3]-dimethyl-L-lysine36 demethylase, [histone H3]-trimethyl-L-lysine9 demethylase, [histone H3]-trimethyl-L-lysine36 demethylase
IDH2	1.1.1.42	isocitrate dehydrogenase (NADP+)

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
IDH1	488
VHL	3,575
KDM4C	122
HIF1A	427

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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	IDH1, IDH2
IVOSIDENIB	4	IDH1, IDH2
VORASIDENIB	4	IDH1, IDH2
OLUTASIDENIB	4	IDH1, IDH2
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
ADAGRASIB	4	VHL
EMETINE	4	HIF1A
DOXORUBICIN	4	HIF1A
TOPOTECAN	4	HIF1A
LEVOSALBUTAMOL	4	HIF1A
LEVODOPA	4	HIF1A
DIENESTROL	4	HIF1A
PROGESTERONE	4	HIF1A
DICLOFENAC SODIUM	4	HIF1A
CLOTRIMAZOLE	4	HIF1A
BUMETANIDE	4	HIF1A
MORICIZINE	4	HIF1A
HYDROCORTISONE ACETATE	4	HIF1A
CHLORMADINONE ACETATE	4	HIF1A
DROPERIDOL	4	HIF1A
AMOXAPINE	4	HIF1A
TORSEMIDE	4	HIF1A
PREDNISOLONE ACETATE	4	HIF1A
BENOXINATE	4	HIF1A
NICARDIPINE HYDROCHLORIDE	4	HIF1A
PHENYLEPHRINE HYDROCHLORIDE	4	HIF1A
SULCONAZOLE NITRATE	4	HIF1A
HYDROXYZINE PAMOATE	4	HIF1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	IDH1, VHL, HIF1A, IDH2
B	Phased (≥1) drug, not yet approved	1	KDM4C
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CDKN2A, COL2A1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CDKN2A	2	—
COL2A1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04134572	Not specified	RECRUITING	Registry of Ollier Disease and Maffucci Syndrome
NCT04844697	Not specified	COMPLETED	Resilience and Coping in a Rare Skeletal Disease Population to Face Coronavirus (COVID-19) Outbreak Distress: a Longitudinal Study