Glioma

Summary

Glioma (MONDO:0021042) is a cancer (an umbrella term covering 9 Mondo subtypes) with 40 cohort genes (368 GWAS associations across 26 studies; 15 CIViC-evidence somatic drivers; 7 ClinVar predisposition records) and 575 clinical trials. The dominant Reactome pathway is Oncogene Induced Senescence (4 cohort genes). Molecularly, IDH2 Mutation OR IDH1 Mutation confers sensitivity to Vorasidenib in Glioma (CIViC Level A); 5 further subtype–drug associations are mapped below. Top therapeutic interventions include lapatinib, larotrectinib, and vorasidenib.

At a glance

• Classification: Cancer
• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 40
• GWAS associations: 368
• ClinVar variants: 7
• Clinical trials: 575
• Precision-medicine evidence (CIViC): 6 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	5.35	Europe	Validated
Point prevalence	1-5 / 10 000	26	Europe	Validated
Annual incidence	1-9 / 100 000	5.26	United States	Validated
Annual incidence	1-9 / 100 000	5.7	Greece	Validated
Annual incidence	1-9 / 100 000	6.2	Croatia	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	glioma
Mondo ID	MONDO:0021042
EFO	EFO:0005543
MeSH	D005910
Orphanet	182067
NCIT	C3059
SNOMED CT	393564001
UMLS	C0017638
MedGen	9030
GARD	0006513
Is cancer (heuristic)	yes

Also known as: glial neoplasm · glial tumor · glial tumour · glioma · neoplasm of neuroglia · neoplasm of the neuroglia · neuroglial neoplasm · neuroglial tumor · neuroglial tumour · tumor of neuroglia · tumor of the neuroglia · tumour of neuroglia · tumour of the neuroglia

Data availability: 7 ClinVar variants · 368 GWAS associations (26 studies).

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › nervous system neoplasm › neuroepithelial neoplasm › glioma

Related subtypes (5): primitive neuroectodermal tumor, papillary tumor of the pineal region, mixed neuronal-glial tumor, neuroepithelioma, pineal parenchymal cell neoplasm

Subtypes (9): nerve sheath neoplasm, ependymal tumor, mixed glioma, optic pathway glioma, astroblastoma, astrocytic tumor, low grade glioma, malignant glioma, diffuse glioma, H3 G34 mutant

Genetics & variants

GWAS landscape

368 GWAS associations across 26 studies. Top hits map to 28 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs55705857	7e-149	CCDC26	G	3.39
rs10069690	3e-66	TERT	T	1.45
rs634537	1e-45	CDKN2B-AS1	G	1.3
rs12803321	6e-43	PHLDB1	G	1.42
rs2297440	2e-42	RTEL1-TNFRSF6B, RTEL1	C	1.36
rs78378222	9e-38	TP53	G	2.53
rs75061358	4e-27	SEC61G-DT - EGFR	G	1.42
rs1938964	5e-19	GRIA4	?	0.62
rs2736100	1e-16	TERT	?	8.28
rs72714270	9e-14	CCDC26	?	7.46
rs77633900	2e-13	ETFA	C	1.35
rs7125115	4e-13	PHLDB1	?	7.25
rs2297433	5e-13	RTEL1, RTEL1-TNFRSF6B	?	7.22
rs11979158	1e-12	EGFR	A	1.4
rs10842893	2e-12	STK38L	T	2.07
rs648044	5e-12	ZBTB16	A	1.19
rs6010620	7e-12	RTEL1-TNFRSF6B, RTEL1	G	1.29
rs10852606	4e-11	HEATR3	C	1.14
rs10131032	5e-11	AKAP6	G	1.33
rs7572263	2e-10	C2orf80	A	1.2
rs10927065	2e-10	AKT3	?	6.38
rs12076373	3e-10	AKT3	G	1.23
rs5839764	3e-10	D2HGDH	?	6.31
rs7107785	4e-10	MAML2	T	1.16
rs139963676	7e-10	HOOK1 - CYP2J2	?	5.18
rs3751667	9e-10	LMF1	T	1.14
rs4975538	1e-09	TERT	?	6.05
rs142721553	2e-09	FGGY	?	4.98
rs4252707	3e-09	MDM4	A	1.19
rs11599775	3e-09	VTI1A	G	1.16

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST004347	Melin BS	2017	12,469	18,190	Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors.
GCST004348	Melin BS	2017	5,819	18,190	Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors.
GCST005931	Ostrom QT	2018	4,831	5,216	Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21.
GCST005932	Ostrom QT	2018	2,835	5,216	Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21.
GCST90296463	Foss-Skiftesvik J	2023	2,473	7,183	Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.
GCST90296473	Foss-Skiftesvik J	2023	2,473	7,183	Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.
GCST001633	Rajaraman P	2012	1,856	4,955	Genome-wide association study of glioma and meta-analysis.
GCST005933	Ostrom QT	2018	1,716	5,216	Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21.
GCST90296464	Foss-Skiftesvik J	2023	1,389	7,183	Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.
GCST90296474	Foss-Skiftesvik J	2023	1,389	7,183	Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	2
Tier 3: regulatory	1
Tier 4: intronic/intergenic	46

MAF distribution

Bucket	Variants
common (>=0.05)	40
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	8

Functional consequences

Consequence	Count
intron_variant	38
intergenic_variant	5
synonymous_variant	2
3_prime_UTR_variant	1
5_prime_UTR_variant	1
non_coding_transcript_exon_variant	1
regulatory_region_variant	1
missense_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs55705857	8	129633446	A>G	0.057	intergenic_variant	CCDC26	7e-149	Tier 4: intronic/intergenic
rs10069690	5	1279675	C>T	0.276	intron_variant	TERT	3e-66	Tier 4: intronic/intergenic
rs634537	9	22032153	T>G	0.411	intron_variant	CDKN2B-AS1	1e-45	Tier 4: intronic/intergenic
rs12803321	11	118609400	G>A,C,T	0.357	intron_variant	PHLDB1	6e-43	Tier 4: intronic/intergenic
rs2297440	20	63680946	T>C	0.204	intron_variant	RTEL1-TNFRSF6B, RTEL1	2e-42	Tier 4: intronic/intergenic
rs78378222	17	7668434	T>A,G	0.013	3_prime_UTR_variant	TP53	9e-38	Tier 2: splice/UTR
rs75061358	7	54848587	T>C,G	0.099	intron_variant	SEC61G-DT - EGFR	4e-27	Tier 4: intronic/intergenic
rs1938964	11	105725550	G>A,T	0.05	intron_variant	GRIA4	5e-19	Tier 4: intronic/intergenic
rs2736100	5	1286401	C>A,G,T	0.05	intron_variant	TERT	1e-16	Tier 4: intronic/intergenic
rs72714270	8	129503207	T>A,G	0.05	intron_variant	CCDC26	9e-14	Tier 4: intronic/intergenic
rs77633900	15	76246118	G>C	0.086	intron_variant	ETFA	2e-13	Tier 4: intronic/intergenic
rs7125115	11	118607615	G>A,C	0.05	5_prime_UTR_variant	PHLDB1	4e-13	Tier 2: splice/UTR
rs2297433	20	63662107	T>C	0.05	intron_variant	RTEL1, RTEL1-TNFRSF6B	5e-13	Tier 4: intronic/intergenic
rs11979158	7	55091656	A>G,T	0.05	intron_variant	EGFR	1e-12	Tier 4: intronic/intergenic
rs10842893	12	27269953	C>T	0.02	intron_variant	STK38L	2e-12	Tier 4: intronic/intergenic
rs648044	11	114160077	A>G,T	0.39	non_coding_transcript_exon_variant	ZBTB16	5e-12	Tier 4: intronic/intergenic
rs6010620	20	63678486	A>C,G,T	0.26	intron_variant	RTEL1-TNFRSF6B, RTEL1	7e-12	Tier 4: intronic/intergenic
rs10852606	16	50094961	T>A,C,G	0.287	intron_variant	HEATR3	4e-11	Tier 4: intronic/intergenic
rs10131032	14	32780875	G>A	0.084	intron_variant	AKAP6	5e-11	Tier 4: intronic/intergenic
rs7572263	2	208186862	A>C,G,T	0.244	intron_variant	C2orf80	2e-10	Tier 4: intronic/intergenic
rs10927065	1	243751309	C>A	0.05	intron_variant	AKT3	2e-10	Tier 4: intronic/intergenic
rs12076373	1	243688645	G>C,T	0.163	intron_variant	AKT3	3e-10	Tier 4: intronic/intergenic
rs5839764	2	241764203	C>G,T	0.05	intron_variant	D2HGDH	3e-10	Tier 4: intronic/intergenic
rs7107785	11	96014174	T>A,C	0.479	intron_variant	MAML2	4e-10	Tier 4: intronic/intergenic
rs139963676	1	59881519	G>A		intergenic_variant	HOOK1 - CYP2J2	7e-10	Tier 4: intronic/intergenic
rs3751667	16	954554	C>T	0.208	synonymous_variant	LMF1	9e-10	Tier 4: intronic/intergenic
rs4975538	5	1280715	G>A,C,T	0.05	intron_variant	TERT	1e-09	Tier 4: intronic/intergenic
rs142721553	1	59773132	C>T		intron_variant	FGGY	2e-09	Tier 4: intronic/intergenic
rs4252707	1	204539019	G>A	0.22	intron_variant	MDM4	3e-09	Tier 4: intronic/intergenic
rs11599775	10	112699938	G>A	0.38	intron_variant	VTI1A	3e-09	Tier 4: intronic/intergenic

ClinVar germline variants

7 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 likely pathogenic, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1195985	t(12;15)(p13;q25)	NTRK3	Pathogenic	no assertion criteria provided
183726	NM_000314.8(PTEN):c.406T>C (p.Cys136Arg)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
186005	NM_000314.8(PTEN):c.70G>C (p.Asp24His)	PTEN	Pathogenic	reviewed by expert panel
404164	NM_000314.8(PTEN):c.445C>T (p.Gln149Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
617751	Single allele	ABHD17B	Likely pathogenic	no assertion criteria provided
930214	t(10;16)(q26;q11)	VPS35	Likely pathogenic	no assertion criteria provided
1195988	NM_002880.4(RAF1):c.673C>T (p.Pro225Ser)	RAF1	Benign	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 104 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
EGFR	Act	BRCA,COADREAD,GB,GBM,HGGNOS,LGGNOS,LUAD,LUSC,NSCLC,PAST,PCM,READ,SIC	CIViC #19
IDH1	Act	AML,CHOL,GB,GBM,HCC,HGGNOS,LGGNOS,MBL,MEL,MT,OS,PAST,PCM,PRAD,SKCM	CIViC #26
H3-3A	Act	HGGNOS,PAST	CIViC #2537
IDH2	Act	AML,BLCA,CHOL,LGGNOS,OS	CIViC #27
TERT	Act	PRCC	CIViC #79
TP53	LoF	ACC,ALL,AML,ANGS,ANSC,BCC,BL,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,EGC,ES,ESCA,ESCC,GB,GBC,GBM,GIST,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LNM,LUAD,LUSC,MBL,MEL,MLYM,MT,NBL,NETNOS,NHL,NPC,NSCLC,OS,OVT,PAAD,PANCREAS,PAST,PCM,PLMESO,PRAD,PRCC,PROSTATE,RCC,READ,SACA,SARCNOS,SCLC,SIC,SKCM,SKIN,SOFT_TISSUE,STAD,STOMACH,THYM,UCEC,UCS,UTUC,VULVA,WDTC,WT	CIViC #45
ZBTB16	Act	ESCC,PRAD
MAML2	ambiguous	AML,LUSC,VULVA
CDKN2A	LoF	ACYC,BLCA,BRCA,CHOL,COAD,COADREAD,CSCC,EGC,ESCA,ESCC,GBM,HCC,HNSC,LGGNOS,LUAD,LUSC,MEL,MLYM,NPC,NSCLC,OS,PAAD,PANCREAS,RCC,SKCM,SKIN,STAD,STOMACH,WDTC	CIViC #14
CDKN2B			CIViC #916
AKT3	Act	PROSTATE,SKCM	CIViC #7936
MDM4			CIViC #3466
MYC	Act	AML,BL,MLYM,NHL	CIViC #3737
NTRK3	Act	ESCC,STAD	CIViC #3985
PTEN	LoF	ANGS,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,COADREAD,CSCC,ESCA,GB,GBM,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LUAD,LUSC,MBL,MEL,MT,NSCLC,OVT,PANET,PAST,PRAD,PRCC,PROSTATE,RCC,SCLC,SKCM,SOFT_TISSUE,STAD,UCEC,UCS,WDTC	CIViC #41

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EGFR	Orphanet:251576	Gliosarcoma
EGFR	Orphanet:251579	Giant cell glioblastoma
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
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
TERC	Orphanet:1775	Dyskeratosis congenita
TERC	Orphanet:2032	Idiopathic pulmonary fibrosis
TERC	Orphanet:88	Idiopathic aplastic anemia
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome
TP53	Orphanet:52688	Myelodysplastic syndrome
TP53	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
TP53	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
TP53	Orphanet:668	Osteosarcoma
TP53	Orphanet:67038	B-cell chronic lymphocytic leukemia
TP53	Orphanet:70573	Small cell lung cancer
TP53	Orphanet:96253	Cushing disease

Cohort genes → proteins

40 cohort genes, 37 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	31
civic_only	2
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EGFR	HGNC:3236	ENSG00000146648	P00533	Epidermal growth factor receptor	gwas,civic_evidence
IDH1	HGNC:5382	ENSG00000138413	O75874	Isocitrate dehydrogenase [NADP] cytoplasmic	gwas,civic_evidence
H3-3A	HGNC:4764	ENSG00000163041	P84243	Histone H3.3	civic_evidence
IDH2	HGNC:5383	ENSG00000182054	P48735	Isocitrate dehydrogenase [NADP], mitochondrial	civic_evidence
TERC	HGNC:11727	ENSG00000270141		telomerase RNA component	gwas
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	gwas
TNFRSF6B	HGNC:11921	ENSG00000243509	O95407	Tumor necrosis factor receptor superfamily member 6B	gwas
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	gwas
ZBTB16	HGNC:12930	ENSG00000109906	Q05516	Zinc finger and BTB domain-containing protein 16	gwas
VPS35	HGNC:13487	ENSG00000069329	Q96QK1	Vacuolar protein sorting-associated protein 35	clinvar
LMF1	HGNC:14154	ENSG00000103227	Q96S06	Lipase maturation factor 1	gwas
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	gwas
MAML2	HGNC:16259	ENSG00000184384	Q8IZL2	Mastermind-like protein 2	gwas
SLC16A8	HGNC:16270	ENSG00000100156	O95907	Monocarboxylate transporter 3	gwas
LRIG1	HGNC:17360	ENSG00000144749	Q96JA1	Leucine-rich repeats and immunoglobulin-like domains protein 1	gwas
VTI1A	HGNC:17792	ENSG00000151532	Q96AJ9	Vesicle transport through interaction with t-SNAREs homolog 1A	gwas
STK38L	HGNC:17848	ENSG00000211455	Q9Y2H1	Serine/threonine-protein kinase 38-like	gwas
CDKN2A	HGNC:1787	ENSG00000147889	P42771	Cyclin-dependent kinase inhibitor 2A	gwas
CDKN2B	HGNC:1788	ENSG00000147883	P42772	Cyclin-dependent kinase 4 inhibitor B	gwas
CYP4F12	HGNC:18857	ENSG00000186204	Q9HCS2	Cytochrome P450 4F12	gwas
RHBDF1	HGNC:20561	ENSG00000007384	Q96CC6	Inactive rhomboid protein 1	gwas
PHLDB1	HGNC:23697	ENSG00000019144	Q86UU1	Pleckstrin homology-like domain family B member 1	gwas
ABHD17B	HGNC:24278	ENSG00000107362	Q5VST6	Alpha/beta hydrolase domain-containing protein 17B	clinvar
RAVER2	HGNC:25577	ENSG00000162437	Q9HCJ3	Ribonucleoprotein PTB-binding 2	gwas
HEATR3	HGNC:26087	ENSG00000155393	Q7Z4Q2	HEAT repeat-containing protein 3	gwas
STN1	HGNC:26200	ENSG00000107960	Q9H668	CST complex subunit STN1	gwas
D2HGDH	HGNC:28358	ENSG00000180902	Q8N465	D-2-hydroxyglutarate dehydrogenase, mitochondrial	gwas
CCDC26	HGNC:28416	ENSG00000229140		CCDC26 long non-coding RNA	gwas
CDKN2B-AS1	HGNC:34341	ENSG00000240498		CDKN2B and CDKN2A antisense cis and trans regulatory RNA 1	gwas
C2orf80	HGNC:34352	ENSG00000188674	Q0P641	Uncharacterized protein C2orf80	gwas
ETFA	HGNC:3481	ENSG00000140374	P13804	Electron transfer flavoprotein subunit alpha, mitochondrial	gwas
AKAP6	HGNC:376	ENSG00000151320	Q13023	A-kinase anchor protein 6	gwas
AKT3	HGNC:393	ENSG00000117020	Q9Y243	RAC-gamma serine/threonine-protein kinase	gwas
GRIA4	HGNC:4574	ENSG00000152578	P48058	Glutamate receptor 4	gwas
MDM4	HGNC:6974	ENSG00000198625	O15151	Protein Mdm4	gwas
MYC	HGNC:7553	ENSG00000136997	P01106	Myc proto-oncogene protein	gwas
NTRK3	HGNC:8033	ENSG00000140538	Q16288	NT-3 growth factor receptor	clinvar
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	clinvar
RAB27A	HGNC:9766	ENSG00000069974	P51159	Ras-related protein Rab-27A	gwas
RAF1	HGNC:9829	ENSG00000132155	P04049	RAF proto-oncogene serine/threonine-protein kinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EGFR	Epidermal growth factor receptor	Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses.
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.
H3-3A	Histone H3.3	Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes.
IDH2	Isocitrate dehydrogenase [NADP], mitochondrial	Plays a role in intermediary metabolism and energy production.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
TNFRSF6B	Tumor necrosis factor receptor superfamily member 6B	Decoy receptor that can neutralize the cytotoxic ligands TNFS14/LIGHT, TNFSF15 and TNFSF6/FASL.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
ZBTB16	Zinc finger and BTB domain-containing protein 16	Acts as a transcriptional repressor.
VPS35	Vacuolar protein sorting-associated protein 35	Acts as a component of the retromer cargo-selective complex (CSC).
LMF1	Lipase maturation factor 1	Involved in the maturation of specific proteins in the endoplasmic reticulum.
RTEL1	Regulator of telomere elongation helicase 1	A probable ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability.
MAML2	Mastermind-like protein 2	Acts as a transcriptional coactivator for NOTCH proteins.
SLC16A8	Monocarboxylate transporter 3	Probable retinal pigment epithelium (RPE)-specific proton-coupled L-lactate transporter.
LRIG1	Leucine-rich repeats and immunoglobulin-like domains protein 1	Acts as a feedback negative regulator of signaling by receptor tyrosine kinases, through a mechanism that involves enhancement of receptor ubiquitination and accelerated intracellular degradation.
VTI1A	Vesicle transport through interaction with t-SNAREs homolog 1A	V-SNARE that mediates vesicle transport pathways through interactions with t-SNAREs on the target membrane.
STK38L	Serine/threonine-protein kinase 38-like	Involved in the regulation of structural processes in differentiating and mature neuronal cells.
CDKN2A	Cyclin-dependent kinase inhibitor 2A	Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6.
CDKN2B	Cyclin-dependent kinase 4 inhibitor B	Interacts strongly with CDK4 and CDK6.
CYP4F12	Cytochrome P450 4F12	A cytochrome P450 monooxygenase involved in the metabolism of endogenous polyunsaturated fatty acids (PUFAs).
RHBDF1	Inactive rhomboid protein 1	Regulates ADAM17 protease, a sheddase of the epidermal growth factor (EGF) receptor ligands and TNF, thereby plays a role in sleep, cell survival, proliferation, migration and inflammation.
ABHD17B	Alpha/beta hydrolase domain-containing protein 17B	Hydrolyzes fatty acids from S-acylated cysteine residues in proteins.
RAVER2	Ribonucleoprotein PTB-binding 2	May bind single-stranded nucleic acids.
HEATR3	HEAT repeat-containing protein 3	Plays a role in ribosome biogenesis and in nuclear import of the 60S ribosomal protein L5/large ribosomal subunit protein uL18 (RPL5).
STN1	CST complex subunit STN1	Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex.
D2HGDH	D-2-hydroxyglutarate dehydrogenase, mitochondrial	Catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to alpha-ketoglutarate.
ETFA	Electron transfer flavoprotein subunit alpha, mitochondrial	Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase.
AKAP6	A-kinase anchor protein 6	Binds to type II regulatory subunits of protein kinase A and anchors/targets them to the nuclear membrane or sarcoplasmic reticulum.
AKT3	RAC-gamma serine/threonine-protein kinase	AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis.
GRIA4	Glutamate receptor 4	Ionotropic glutamate receptor that functions as a ligand-gated cation channel, gated by L-glutamate and glutamatergic agonists such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), quisqualic acid, and kainic acid.
MDM4	Protein Mdm4	Contributes to p53/TP53 regulation.
MYC	Myc proto-oncogene protein	Transcription factor that binds DNA in a non-specific manner, yet also specifically recognizes the core sequence 5’-CAC[GA]TG-3'.
NTRK3	NT-3 growth factor receptor	Receptor tyrosine kinase involved in nervous system and probably heart development.
PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins.
RAB27A	Ras-related protein Rab-27A	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
RAF1	RAF proto-oncogene serine/threonine-protein kinase	Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including prolifer…

Protein-family classification

Druggable: 13 · Difficult: 7 · Unknown: 20 · Druggable fraction: 0.33

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
Kinase	5	3.5×	0.126
Phosphatase	1	2.1×	0.775
Transporter	1	1.9×	0.775
Scaffold/PPI	3	1.3×	0.775
Enzyme (other)	4	1.2×	0.775
Protease	1	0.9×	0.816
Other/Unknown	20	0.9×	0.816
Transcription factor	4	0.8×	0.816
Antibody/Immunoglobulin	1	0.7×	0.816

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EGFR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
IDH1	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
H3-3A	Other/Unknown	no		Histone_H3/CENP-A, H2A/H2B/H3, Histone-fold
IDH2	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
TERC	Other/Unknown	no
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
TNFRSF6B	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFRSF6B_N, TNFRSF_decoy_receptor
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
ZBTB16	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
VPS35	Other/Unknown	no		Vps35, ARM-type_fold, Vps35_C
LMF1	Other/Unknown	no		LMF, LMF1/2_C, LMF1/2_N
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
MAML2	Other/Unknown	no		Mastermind-like_N, MAML1-3, MAML_N_sf
SLC16A8	Transporter	yes		MCT, MFS, MFS_dom
LRIG1	Antibody/Immunoglobulin	yes		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt
VTI1A	Other/Unknown	no		T_SNARE_dom, Vesicle_trsprt_v-SNARE_N, SNARE
STK38L	Kinase	yes		Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS
CDKN2A	Scaffold/PPI	no		Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor, Tumor_suppres_ARF
CDKN2B	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor
CYP4F12	Enzyme (other)	yes	1.14.14.B9	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
RHBDF1	Protease	yes		iRhom1_2_N, Peptidase_S54_rhomboid_dom, Rhomboid-like_sf
PHLDB1	Scaffold/PPI	no		FHA_dom, PH_domain, SMAD_FHA_dom_sf
ABHD17B	Other/Unknown	no		ABHD17C-like, AB_hydrolase_fold
RAVER2	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RAVER2_RRM2
HEATR3	Other/Unknown	no		ARM-like, ARM-type_fold, SYO1-like
STN1	Other/Unknown	no		NA-bd_OB_tRNA, NA-bd_OB-fold, Stn1
D2HGDH	Enzyme (other)	yes	1.1.99.39	FAD-bd_oxidored_4_C, Oxid_FAD_bind_N, FAD-linked_Oxase-like_C
CCDC26	Other/Unknown	no
CDKN2B-AS1	Other/Unknown	no
C2orf80	Other/Unknown	no		C2orf80
ETFA	Other/Unknown	no		ETF_a/FixB, Rossmann-like_a/b/a_fold, ETF_a/b_N
AKAP6	Other/Unknown	no		Spectrin_repeat, Spectrin/alpha-actinin
AKT3	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain
GRIA4	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
MDM4	Transcription factor	no		Znf_RING, Znf_RanBP2, SWIB_MDM2_domain
MYC	Transcription factor	no		Tscrpt_reg_Myc, Myc-LZ, bHLH_dom
NTRK3	Kinase	yes	2.7.10.1	LRRNT, Cys-rich_flank_reg_C, Prot_kinase_dom
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom
RAB27A	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
RAF1	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE

Expression context

Cohort genes with no expression data: 0.

36 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)	40
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	5
jejunal mucosa	4
sural nerve	4
monocyte	3
gastrocnemius	3
colonic epithelium	3
male germ line stem cell (sensu Vertebrata) in testis	3
secondary oocyte	3
calcaneal tendon	3
mucosa of transverse colon	3
endothelial cell	3
nipple	2
adrenal tissue	2
ganglionic eminence	2
bone marrow cell	2
tendon of biceps brachii	2
Brodmann (1909) area 23	2
right uterine tube	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EGFR	285	ubiquitous	marker	nipple, gingiva, gingival epithelium
IDH1	294	ubiquitous	marker	corpus epididymis, jejunal mucosa, adrenal tissue
H3-3A	134	ubiquitous	marker	ganglionic eminence, monocyte, ventricular zone
IDH2	292	ubiquitous	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle
TERC	113	ubiquitous	yes	bone marrow cell, colonic epithelium, male germ line stem cell (sensu Vertebrata) in testis
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
TNFRSF6B	127	broad	yes	olfactory segment of nasal mucosa, spleen, subcutaneous adipose tissue
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
ZBTB16	281	broad	marker	skin of hip, Brodmann (1909) area 23, tibialis anterior
VPS35	149	ubiquitous	marker	ventricular zone, adrenal tissue, corpus callosum
LMF1	276	ubiquitous	marker	right uterine tube, C1 segment of cervical spinal cord, sural nerve
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
MAML2	238	ubiquitous	marker	mucosa of paranasal sinus, cartilage tissue, mammary duct
SLC16A8	169	tissue_specific	marker	pigmented layer of retina, male germ line stem cell (sensu Vertebrata) in testis, nucleus accumbens
LRIG1	290	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, ventricular zone
VTI1A	240	ubiquitous	marker	sural nerve, calcaneal tendon, pancreatic ductal cell
STK38L	289	ubiquitous	marker	ascending aorta, thoracic aorta, aorta
CDKN2A	220	ubiquitous	marker	parotid gland, cervix squamous epithelium, pituitary gland
CDKN2B	219	ubiquitous	marker	jejunal mucosa, colonic mucosa, lower esophagus mucosa
CYP4F12	259	broad	marker	mucosa of transverse colon, ileal mucosa, tongue squamous epithelium
RHBDF1	266	ubiquitous	marker	tibial nerve, popliteal artery, tibial artery
PHLDB1	281	ubiquitous	marker	sural nerve, tibial nerve, middle frontal gyrus
ABHD17B	264	ubiquitous	marker	endothelial cell, secondary oocyte, epithelium of nasopharynx
RAVER2	236	ubiquitous	marker	jejunal mucosa, rectum, mucosa of transverse colon
HEATR3	248	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
STN1	284	ubiquitous	marker	lower esophagus mucosa, oral cavity, esophagus mucosa
D2HGDH	223	ubiquitous	marker	right uterine tube, pancreatic ductal cell, tendon of biceps brachii
CCDC26	160	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium, bone marrow cell
CDKN2B-AS1	169	ubiquitous	marker	mucosa of transverse colon, rectum, transverse colon
C2orf80	125	tissue_specific	marker	endothelial cell, middle temporal gyrus, dorsolateral prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 28.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
MYC	20,608
EGFR	18,421
PTEN	11,626
CDKN2A	9,311
RAF1	6,574
TERT	5,717
IDH1	5,464
IDH2	4,912
NTRK3	4,147

Intra-cohort edges

A	B	Sources
AKT3	PTEN	string_interaction
C2orf80	HEATR3	string_interaction
C2orf80	PHLDB1	string_interaction
CDKN2A	CDKN2B	biogrid_interaction
CDKN2A	MDM4	string_interaction
CDKN2A	MYC	string_interaction
CDKN2A	PHLDB1	string_interaction
CDKN2A	TP53	string_interaction
CDKN2B	PHLDB1	string_interaction
CDKN2B	TP53	string_interaction
D2HGDH	IDH1	string_interaction
D2HGDH	IDH2	string_interaction
EGFR	HEATR3	intact
EGFR	IDH2	biogrid_interaction
EGFR	LRIG1	biogrid_interaction, intact, string_interaction
EGFR	PHLDB1	string_interaction
EGFR	PTEN	string_interaction
IDH1	IDH2	biogrid_interaction
IDH1	MDM4	string_interaction
IDH1	PTEN	string_interaction
IDH1	TP53	string_interaction
LRIG1	ZBTB16	biogrid_interaction
MDM4	TP53	biogrid_interaction, intact, string_interaction
MYC	TP53	string_interaction
PHLDB1	RTEL1	string_interaction
PHLDB1	TERT	string_interaction
PTEN	TP53	string_interaction
RTEL1	TERT	string_interaction

Structural data

PDB: 25 · AlphaFold-only: 12 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EGFR	P00533	388
TP53	P04637	313
H3-3A	P84243	103
RAF1	P04049	76
IDH1	O75874	61
MDM4	O15151	39
MYC	P01106	25
TERT	O14746	23
VPS35	Q96QK1	13
PTEN	P60484	12
IDH2	P48735	11
RAB27A	P51159	11
TNFRSF6B	O95407	8
STN1	Q9H668	8
D2HGDH	Q8N465	6
CDKN2A	P42771	5
NTRK3	Q16288	5
ETFA	P13804	4
ZBTB16	Q05516	3
RTEL1	Q9NZ71	3
LRIG1	Q96JA1	2
RHBDF1	Q96CC6	2
AKT3	Q9Y243	2
STK38L	Q9Y2H1	1
RAVER2	Q9HCJ3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABHD17B	Q5VST6	92.51
CYP4F12	Q9HCS2	90.97
LMF1	Q96S06	90.49
CDKN2B	P42772	90.12
VTI1A	Q96AJ9	85.00
GRIA4	P48058	83.24
HEATR3	Q7Z4Q2	83.07
SLC16A8	O95907	77.38
PHLDB1	Q86UU1	60.40
C2orf80	Q0P641	53.43
MAML2	Q8IZL2	46.21
AKAP6	Q13023	43.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 358. Enrichment computed across 40 evidence-associated genes (30 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 30 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Oncogene Induced Senescence	4	44.8×	3e-04	TP53, CDKN2A, CDKN2B, MDM4
Cell Cycle	8	9.6×	3e-04	TERT, RTEL1, CDKN2A, CDKN2B, STN1, AKT3, MDM4, MYC
Regulation of TP53 Degradation	4	39.0×	4e-04	TP53, CDKN2A, AKT3, MDM4
Stabilization of p53	3	76.1×	7e-04	TP53, CDKN2A, MDM4
Extension of Telomeres	3	60.1×	1e-03	TERT, RTEL1, STN1
Mitotic G1 phase and G1/S transition	4	24.6×	1e-03	CDKN2A, CDKN2B, AKT3, MYC
Oxidative Stress Induced Senescence	5	15.1×	1e-03	TP53, CDKN2A, CDKN2B, H3-3A, MDM4
Regulation of TP53 Expression and Degradation	3	51.9×	0.001	CDKN2A, AKT3, MDM4
Telomere Maintenance	3	36.8×	0.003	TERT, RTEL1, STN1
Transcriptional regulation by RUNX3	3	27.2×	0.006	MAML2, CDKN2A, MYC
Chromosome Maintenance	3	21.1×	0.012	TERT, RTEL1, STN1
Regulation of TP53 Activity through Association with Co-factors	2	54.4×	0.018	TP53, AKT3
Regulation of beta-cell development	2	47.6×	0.019	MAML2, AKT3
p53-Dependent G1 DNA Damage Response	2	47.6×	0.019	CDKN2A, MDM4
p53-Dependent G1/S DNA damage checkpoint	2	47.6×	0.019	CDKN2A, MDM4
G1/S DNA Damage Checkpoints	2	44.8×	0.020	CDKN2A, MDM4
Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate	1	380.7×	0.023	IDH1
Evasion of Oncogene Induced Senescence Due to p14ARF Defects	1	380.7×	0.023	CDKN2A
Evasion of Oxidative Stress Induced Senescence Due to p14ARF Defects	1	380.7×	0.023	CDKN2A
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	380.7×	0.023	TP53
SUMOylation of transcription factors	2	38.1×	0.023	TP53, CDKN2A
Regulation of TP53 Activity through Methylation	2	36.2×	0.023	TP53, MDM4
Telomere Extension By Telomerase	2	30.4×	0.023	TERT, RTEL1
Regulation of TP53 Activity through Acetylation	2	30.4×	0.023	TP53, AKT3
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	2	29.3×	0.023	EGFR, AKT3
Signaling by NOTCH1 PEST Domain Mutants in Cancer	2	27.2×	0.023	MAML2, MYC
Signaling by NOTCH1 in Cancer	2	27.2×	0.023	MAML2, MYC
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	2	27.2×	0.023	MAML2, MYC
G1 Phase	2	26.2×	0.023	CDKN2A, CDKN2B
Cellular response to chemical stress	3	14.3×	0.023	CDKN2A, AKT3, MYC

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 35 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	481.5×	9e-04	IDH1, IDH2
replicative senescence	3	85.0×	9e-04	TERT, TP53, CDKN2A
2-oxoglutarate metabolic process	3	80.2×	9e-04	IDH1, D2HGDH, IDH2
positive regulation of miRNA transcription	4	33.2×	9e-04	EGFR, TERT, TP53, MYC
negative regulation of cell population proliferation	7	8.4×	0.002	TP53, ZBTB16, CDKN2A, CDKN2B, MDM4, PTEN, RAF1
negative regulation of cellular senescence	3	55.6×	0.002	TERT, AKT3, PTEN
regulation of dendritic spine maintenance	2	240.7×	0.002	VPS35, ABHD17B
isocitrate metabolic process	2	192.6×	0.003	IDH1, IDH2
negative regulation of apoptotic process	7	7.0×	0.003	EGFR, TNFRSF6B, TP53, AKT3, MDM4, MYC, RAF1
voluntary musculoskeletal movement	2	160.5×	0.004	VPS35, VTI1A
postsynaptic density assembly	2	107.0×	0.008	NTRK3, PTEN
negative regulation of glial cell proliferation	2	96.3×	0.008	TP53, IDH2
regulation of protein stability	4	14.4×	0.008	TERT, VPS35, CDKN2A, PTEN
cellular response to hypoxia	4	13.9×	0.008	TERT, TP53, MDM4, MYC
NADP+ metabolic process	2	87.5×	0.008	IDH1, IDH2
cellular senescence	3	25.3×	0.008	TP53, CDKN2A, CDKN2B
protein destabilization	3	24.9×	0.008	VPS35, CDKN2A, D2HGDH
telomere maintenance	3	22.9×	0.010	TERT, RTEL1, STN1
type II interferon-mediated signaling pathway	2	68.8×	0.011	TP53, RAF1
rRNA transcription	2	56.6×	0.016	TP53, CDKN2A
regulation of mitochondrion organization	2	48.1×	0.021	VPS35, AKT3
DNA strand displacement	1	481.5×	0.022	RTEL1
RNA-templated transcription	1	481.5×	0.022	TERT
DNA strand elongation	1	481.5×	0.022	TERT
multivesicular body organization	1	481.5×	0.022	RAB27A
cytotoxic T cell degranulation	1	481.5×	0.022	RAB27A
positive regulation of axon extension involved in regeneration	1	481.5×	0.022	NTRK3
negative regulation of helicase activity	1	481.5×	0.022	TP53
regulation of cellular component organization	1	481.5×	0.022	STK38L
regulation of phospholipid catabolic process	1	481.5×	0.022	IDH1

Therapeutics

Drugs indicated for this disease

4 approved, 3 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Carmustine	Approved (phase 4)
Iopamidol	Approved (phase 4)
Temozolomide	Approved (phase 4)
Tovorafenib	Approved (phase 4)
Carboplatin	Phase 3 (in late-stage trials)
Magnesium Sulfate Anhydrous	Phase 3 (in late-stage trials)
Vincristine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): ANTINEOPLASTON A10, Acetaminophen, Amino Acids, Armodafinil, Bevacizumab, Capecitabine, Catequentinib, Cetuximab, Cisplatin, Dasatinib Anhydrous, Doxorubicin, Endostatin, Enzastaurin, Etoposide, Etoposide Phosphate, Everolimus, Futuximab, Gemcitabine, Granisetron, Ibuprofen, Irinotecan, Lenalidomide, Lomustine, Nilotinib, Nivolumab, Olaparib, Ondansetron, Paclitaxel, Palonosetron, Panobinostat, Regramostim, Rilotumumab, Rindopepimut, Rivoceranib, Streptozocin, Sunitinib, Valacyclovir, Valproic Acid, Veliparib, Vinblastine, Vinorelbine.

Drug target analysis

Approved (phase 4): 12 · Phase ≥3: 13 · Phased (≥1): 14 · Undrugged: 26

Druggability breadth: 23 of 40 evidence-associated genes (58%) 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
EGFR	LEVODOPA
IDH1	ENASIDENIB
IDH2	ENASIDENIB
TERT	BERBERINE
TP53	NITROFURANTOIN
STK38L	SUNITINIB
AKT3	CAPIVASERTIB
GRIA4	CYCLOTHIAZIDE
MDM4	DIOSMIN
NTRK3	FEDRATINIB
RAB27A	COPANLISIB
RAF1	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
EGFR	175	4
NTRK3	41	4
RAF1	31	4
AKT3	18	4
IDH1	10	4
TERT	10	4
STK38L	8	4
IDH2	7	4
GRIA4	7	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LEVODOPA	4	EGFR
CLOTRIMAZOLE	4	EGFR, TP53
ERLOTINIB HYDROCHLORIDE	4	EGFR
CISPLATIN	4	EGFR
PONATINIB	4	EGFR
AFATINIB	4	EGFR
CHROMIC CHLORIDE	4	EGFR
BACITRACIN	4	EGFR
ZINC CHLORIDE	4	EGFR
LAPATINIB DITOSYLATE	4	EGFR
VEMURAFENIB	4	EGFR, RAF1
FEDRATINIB	4	EGFR, NTRK3
AXITINIB	4	EGFR
SORAFENIB	4	EGFR, NTRK3, RAF1
DASATINIB ANHYDROUS	4	EGFR
NICLOSAMIDE	4	EGFR, TP53
SELUMETINIB	4	EGFR
TERFENADINE	4	EGFR
ALECTINIB	4	EGFR
NERATINIB	4	EGFR
IBRUTINIB	4	EGFR
AFATINIB DIMALEATE	4	EGFR
CABOZANTINIB	4	EGFR
DACOMITINIB	4	EGFR
DACOMITINIB ANHYDROUS	4	EGFR
CERITINIB	4	EGFR
VANDETANIB	4	EGFR
TRIBROMSALAN	4	EGFR
BOSUTINIB	4	EGFR, NTRK3
BITHIONOL	4	EGFR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 9.

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

Symbol	Assays	Type breakdown
EGFR	6,531	Binding:6211, Functional:173, ADMET:138, Toxicity:9
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
RAF1	839	Binding:803, Functional:31, ADMET:5
AKT3	660	Binding:644, Functional:16
IDH1	488	Binding:475, Functional:12, ADMET:1
NTRK3	408	Binding:400, Functional:4, ADMET:4
TERT	391	Binding:389, Functional:2
MYC	202	Binding:202
STK38L	201	Binding:201
MDM4	149	Binding:148, Functional:1
GRIA4	102	Binding:83, Functional:19
IDH2	84	Binding:84
VPS35	11	Binding:11
CYP4F12	11	ADMET:11
PTEN	8	Binding:8
H3-3A	6	Binding:6
ZBTB16	3	Binding:3
ABHD17B	3	Binding:3
RAB27A	3	Binding:3
SLC16A8	2	Binding:2
CDKN2A	2	Binding:2
PHLDB1	1	Binding:1
ETFA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EGFR	2.7.10.1	receptor protein-tyrosine kinase
IDH1	1.1.1.42	isocitrate dehydrogenase (NADP+)
IDH2	1.1.1.42	isocitrate dehydrogenase (NADP+)
CYP4F12	1.14.14.B9
D2HGDH	1.1.99.39	D-2-hydroxyglutarate dehydrogenase
AKT3	2.7.11.1	non-specific serine/threonine protein kinase
NTRK3	2.7.10.1	receptor protein-tyrosine kinase
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase
RAF1	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EGFR	6,531
IDH1	488
TERT	391
TP53	869
STK38L	201
AKT3	660
GRIA4	102
MDM4	149
MYC	202
NTRK3	408
RAF1	839

Pharmacogenomics

Cohort genes with a PharmGKB record: 40; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

27 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
LEVODOPA	4	EGFR
CLOTRIMAZOLE	4	EGFR, TP53
ERLOTINIB HYDROCHLORIDE	4	EGFR
CISPLATIN	4	EGFR
PONATINIB	4	EGFR
CHROMIC CHLORIDE	4	EGFR
BACITRACIN	4	EGFR
ZINC CHLORIDE	4	EGFR
LAPATINIB DITOSYLATE	4	EGFR
FEDRATINIB	4	EGFR, NTRK3
AXITINIB	4	EGFR
SORAFENIB	4	EGFR, NTRK3, RAF1
DASATINIB ANHYDROUS	4	EGFR
NICLOSAMIDE	4	EGFR, TP53
TERFENADINE	4	EGFR
ALECTINIB	4	EGFR
NERATINIB	4	EGFR
IBRUTINIB	4	EGFR
AFATINIB DIMALEATE	4	EGFR
CABOZANTINIB	4	EGFR
DACOMITINIB	4	EGFR
DACOMITINIB ANHYDROUS	4	EGFR
CERITINIB	4	EGFR
VANDETANIB	4	EGFR
TRIBROMSALAN	4	EGFR
BOSUTINIB	4	EGFR, NTRK3
BITHIONOL	4	EGFR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	12	EGFR, IDH1, IDH2, TERT, TP53, STK38L, AKT3, GRIA4, MDM4, NTRK3 (+2 more)
B	Phased (≥1) drug, not yet approved	2	VPS35, MYC
C	Druggable family + PDB, no drug	4	LRIG1, RHBDF1, D2HGDH, PTEN
D	Druggable family + AlphaFold only, no drug	2	SLC16A8, CYP4F12
E	Difficult family or no structure, no drug	20	H3-3A, TERC, TNFRSF6B, ZBTB16, LMF1, RTEL1, MAML2, VTI1A, CDKN2A, CDKN2B (+10 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LRIG1	0	EGFR
CDKN2B	0	TP53
PHLDB1	1	TERT
D2HGDH	0	IDH2, IDH1
PTEN	8	TP53
H3-3A	6	—
TERC	0	—
TNFRSF6B	0	—
ZBTB16	3	—
LMF1	0	—
RTEL1	0	—
MAML2	0	—
SLC16A8	2	—
VTI1A	0	—
CDKN2A	2	—
CYP4F12	11	—
RHBDF1	0	—
ABHD17B	3	—
RAVER2	0	—
HEATR3	0	—
STN1	0	—
CCDC26	0	—
CDKN2B-AS1	0	—
C2orf80	0	—
ETFA	1	—
AKAP6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 575.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	285
PHASE2	100
PHASE1	96
PHASE1/PHASE2	35
EARLY_PHASE1	33
PHASE3	15
PHASE2/PHASE3	8
PHASE4	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03048084	PHASE4	RECRUITING	Seizure Treatment in Glioma
NCT07486713	PHASE4	RECRUITING	Olutasidenib DDI Study in Patients With IDH1 Mutation Positive Malignancies
NCT06625047	PHASE4	COMPLETED	Comparing Telehealth and In-person Assessments in Glioma Patients Receiving Oral Chemotherapy
NCT04164901	PHASE3	ACTIVE_NOT_RECRUITING	Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)
NCT05303519	PHASE3	RECRUITING	SIGMA (Safusidenib in IDH1 Mutant Glioma Maintenance)
NCT05512403	PHASE3	RECRUITING	Evaluation of Diagnostic Performances of 18F-FDOPA PET KInetics
NCT05580562	PHASE3	RECRUITING	ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study)
NCT05768178	PHASE2/PHASE3	RECRUITING	DETERMINE Trial Treatment Arm 05: Vemurafenib in Combination With Cobimetinib in Adult Patients With BRAF Positive Cancers.
NCT05770544	PHASE2/PHASE3	RECRUITING	DETERMINE Trial Treatment Arm 03: Entrectinib in Adult, Paediatric and Teenage/Young Adult Patients With ROS1 Gene Fusion-Positive Cancers.
NCT06330337	PHASE3	RECRUITING	Effect of Electroacupuncture Combined With Paclitaxel Clinical Efficacy of Patients With Recurrence of High-grade Glioma
NCT06496971	PHASE3	RECRUITING	A Prospective Pivotal Study to Evaluate the Efficacy and Safety of Avastin® Bevacizumab (BEV) With or Without Microbubble-mediated Focused Ultrasound (FUS-MB) Using NaviFUS System in Recurrent Glioblastoma Multiforme Patients
NCT06750458	PHASE3	NOT_YET_RECRUITING	Dapagliflozin Versus Dexamethasone Role in Pre-operative Management of Non- Diabetic Brain Tumor Patients
NCT06988475	PHASE2/PHASE3	RECRUITING	DETERMINE Trial Treatment Arm 06: Capmatinib in Adult Patients With Cancers Harbouring MET Dysregulations
NCT07440290	PHASE2/PHASE3	NOT_YET_RECRUITING	DETERMINE Trial Treatment Arm 07: Dabrafenib in Combination With Trametinib in Adult, Paediatric and Teenage/Young Adult Patients With BRAF V600 Mutation-Positive Cancers.
NCT00045968	PHASE3	UNKNOWN	Study of a Drug [DCVax®-L] to Treat Newly Diagnosed GBM Brain Cancer
NCT00256425	PHASE3	UNKNOWN	Cognitive Rehabilitation of Glioma Patients
NCT01460706	PHASE2/PHASE3	COMPLETED	Imaging Malignant Glioma With 68Ga-DOTATOC PET/CT
NCT01479686	PHASE3	COMPLETED	iMRI Guided Resection in Cerebral Glioma Surgery
NCT01502280	PHASE3	COMPLETED	Fluorescence-guided Surgery for Low- and High-grade Gliomas
NCT01655927	PHASE3	UNKNOWN	Efficacy of Tranexamic Acid in Brain Tumor Resections
NCT01961934	PHASE2/PHASE3	WITHDRAWN	C11-Sodium Acetate PET/CT Imaging Evaluation in Brain Glioma, Post Therapy Necrosis and Pseudo-progression
NCT02363075	PHASE3	UNKNOWN	Dexamfetamine Sulphate in Patients With Glioma Suffering From Severe Asthenia
NCT02678975	PHASE2/PHASE3	COMPLETED	Disulfiram in Recurrent Glioblastoma
NCT02879682	PHASE2/PHASE3	COMPLETED	nTMS for Motor Mapping of Rolandic Lesions
NCT03149575	PHASE3	TERMINATED	VAL-083 Phase 3 Study in Temozolomide-Avastin (Bevacizumab) Recurrent GBM
NCT03722355	PHASE3	COMPLETED	Hyperfractionated RT With BCNU Versus Conventional RT With BCNU for Supratentorial Malignant Glioma
NCT01906385	PHASE1/PHASE2	RECRUITING	Maximum Tolerated Dose, Safety, and Efficacy of Rhenium Nanoliposomes in Recurrent Glioma (ReSPECT)
NCT02465060	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)
NCT02800486	PHASE2	RECRUITING	Super Selective Intra-arterial Repeated Infusion of Cetuximab (Erbitux) With Reirradiation for Treatment of Relapsed/Refractory GBM, AA, and AOA
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03180502	PHASE2	ACTIVE_NOT_RECRUITING	Proton Beam or Intensity-Modulated Radiation Therapy in Preserving Brain Function in Patients With IDH Mutant Grade II or III Glioma
NCT03212274	PHASE2	ACTIVE_NOT_RECRUITING	Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03687957	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	rhIL-7-hyFc on Increasing Lymphocyte Counts in Patients With Newly Diagnosed Non-severe Lymphopenic Gliomas Following Radiation and Temozolomide
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT03718767	PHASE2	ACTIVE_NOT_RECRUITING	Nivolumab in Patients With IDH-Mutant Gliomas With and Without Hypermutator Phenotype
NCT03728673	PHASE2	RECRUITING	A Study Utilizing Escitalopram in Glioma Patients
NCT03991832	PHASE2	RECRUITING	Study of Olaparib and Durvalumab in IDH-Mutated Solid Tumors
NCT05188508	PHASE2	RECRUITING	Pembrolizumab, Olaparib, and Temozolomide for People With Glioma
NCT05345002	PHASE2	RECRUITING	All-Trans Retinoic Acid (ATRA) Plus PD-1 Inhibition in Recurrent IDH-Mutant Glioma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LAPATINIB	4	6
LAROTRECTINIB	4	6
VORASIDENIB	4	5
AMINOLEVULINIC ACID	4	4
IVOSIDENIB	4	4
AFATINIB	4	3
DABRAFENIB	4	3
ERDAFITINIB	4	3
PANOBINOSTAT	4	3
SELUMETINIB	4	3
CARMUSTINE	4	2
LOMUSTINE	4	2
RETIFANLIMAB	4	2
RIBOCICLIB	4	2
SONIDEGIB	4	2
TAZEMETOSTAT	4	2
TRAMETINIB	4	2
VALPROIC ACID	4	2
VEMURAFENIB	4	2
APREPITANT	4	1
BINIMETINIB	4	1
CAPIVASERTIB	4	1
CAPMATINIB	4	1
COBIMETINIB	4	1
COPANLISIB	4	1
COPANLISIB HYDROCHLORIDE	4	1
COPPER	4	1
CRIZOTINIB	4	1
CYSTEINE	4	1
DEXTROAMPHETAMINE	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 6 predictive associations from 6 curated evidence items; also 4 prognostic, 2 diagnostic.

Molecular subtype	Therapy	Effect	Level	CIViC
IDH2 Mutation OR IDH1 Mutation	Vorasidenib	Sensitivity/Response	CIViC A	EID11708
H3-3A K28M	Dordaviprone	Sensitivity/Response	CIViC B	EID7601
IDH1 R132	Safusidenib	Sensitivity/Response	CIViC B	EID7448
EGFR Overexpression	Gefitinib + Radiation Therapy	Sensitivity/Response	CIViC D	EID7803
HOXC10 Overexpression	Bevacizumab	Sensitivity/Response	CIViC D	EID9949
HSP90B1 Overexpression	Onalespib + Temozolomide	Sensitivity/Response	CIViC D	EID10153