Tuberous sclerosis 2

Summary

Tuberous sclerosis 2 (MONDO:0013199) is a disease caused by TSC2 (GenCC Definitive), with 19 cohort genes and 4 clinical trials. Top therapeutic interventions include everolimus.

At a glance

• Causal gene: TSC2 (GenCC Definitive)
• Cohort genes: 19
• ClinVar variants: 9,883
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	tuberous sclerosis 2
Mondo ID	MONDO:0013199
MeSH	C566021
OMIM	613254
DOID	DOID:0080325
NCIT	C75331
UMLS	C1860707
MedGen	348170
GARD	0015640
Is cancer (heuristic)	no

Also known as: TSC2 · TSC2-related tuberous sclerosis · tuberous sclerosis 2 · tuberous sclerosis type 2 · tuberous sclerosis, type 2 · tuberous sclerosis-2

Data availability: 9,883 ClinVar variants · 5 GenCC gene-disease records · 49 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › tuberous sclerosis › tuberous sclerosis 2

Related subtypes (1): tuberous sclerosis 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

600 retrieved; paginated sample, class counts are floors:

285 uncertain significance, 103 likely benign, 69 benign/likely benign, 67 conflicting classifications of pathogenicity, 46 pathogenic, 14 not provided, 7 likely pathogenic, 5 benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069475	NC_000016.9:g.(?2103323)(2185710_?)del	MIR1225	Pathogenic	criteria provided, single submitter
1073183	NC_000016.9:g.(?2089925)(2114438_?)del	NTHL1	Pathogenic	criteria provided, single submitter
100923	NM_000488.4(SERPINC1):c.1016G>A (p.Trp339Ter)	SERPINC1	Pathogenic	reviewed by expert panel
1028339	NM_000548.5(TSC2):c.1258-2A>G	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1028343	NM_000548.5(TSC2):c.600-2A>T	TSC2	Pathogenic	criteria provided, single submitter
1042872	NM_000548.5(TSC2):c.3179G>C (p.Trp1060Ser)	TSC2	Pathogenic	criteria provided, single submitter
1045993	NM_000548.5(TSC2):c.4930G>T (p.Asp1644Tyr)	TSC2	Pathogenic	criteria provided, single submitter
1066434	NM_000548.5(TSC2):c.1945_1946+4del	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067682	NM_000548.5(TSC2):c.2837+1G>A	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068040	NM_000548.5(TSC2):c.4834_4850-95del	TSC2	Pathogenic	criteria provided, single submitter
1068227	NM_000548.5(TSC2):c.551T>A (p.Val184Asp)	TSC2	Pathogenic	criteria provided, single submitter
1068835	NM_000548.5(TSC2):c.3397+1G>T	TSC2	Pathogenic	criteria provided, single submitter
1069474	NC_000016.9:g.(?2103337)(2110820_?)del	TSC2	Pathogenic	criteria provided, single submitter
1069644	NM_000548.5(TSC2):c.4827C>A (p.Cys1609Ter)	TSC2	Pathogenic	criteria provided, single submitter
1069923	NM_000548.5(TSC2):c.5377_5378insT (p.Arg1793fs)	TSC2	Pathogenic	criteria provided, single submitter
1069935	NM_000548.5(TSC2):c.138+5G>C	TSC2	Pathogenic	criteria provided, single submitter
1070034	NM_000548.5(TSC2):c.4013_4014del (p.Ser1338fs)	TSC2	Pathogenic	criteria provided, single submitter
1070242	NM_000548.5(TSC2):c.5103_5104del (p.Lys1701fs)	TSC2	Pathogenic	criteria provided, single submitter
1070243	NM_000548.5(TSC2):c.3434del (p.Pro1145fs)	TSC2	Pathogenic	criteria provided, single submitter
1071233	NM_000548.5(TSC2):c.2687_2690dup (p.Phe897fs)	TSC2	Pathogenic	criteria provided, single submitter
1071355	NM_000548.5(TSC2):c.3505del (p.Ala1169fs)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1071378	NC_000016.9:g.(?_2025180)_2130380del	TSC2	Pathogenic	criteria provided, single submitter
1071380	NC_000016.9:g.(?2120437)(2123004_?)del	TSC2	Pathogenic	criteria provided, single submitter
1071381	NC_000016.9:g.(?2098597)(2108894_?)del	TSC2	Pathogenic	criteria provided, single submitter
1072019	NM_000548.5(TSC2):c.810_811dup (p.Ser271fs)	TSC2	Pathogenic	criteria provided, single submitter
1072368	NM_000548.5(TSC2):c.2166dup (p.Ile723fs)	TSC2	Pathogenic	criteria provided, single submitter
1072481	NM_000548.5(TSC2):c.4756del (p.Asp1586fs)	TSC2	Pathogenic	criteria provided, single submitter
1072488	NM_000548.5(TSC2):c.3610+1G>T	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072663	NM_000548.5(TSC2):c.3582G>A (p.Trp1194Ter)	TSC2	Pathogenic	criteria provided, single submitter
1072814	NM_000548.5(TSC2):c.2285T>A (p.Leu762Ter)	TSC2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 34 · 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
TSC2	Definitive	Autosomal dominant	tuberous sclerosis 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSC2	Orphanet:210159	Adult hepatocellular carcinoma
TSC2	Orphanet:269001	Isolated focal cortical dysplasia type IIa
TSC2	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC2	Orphanet:538	Lymphangioleiomyomatosis
TSC2	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
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
CCDC78	Orphanet:319160	Congenital myopathy with internal nuclei and atypical cores
GFER	Orphanet:330054	Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome
IFNG	Orphanet:699618	Severe mendelian susceptibility to mycobacterial diseases due to complete IFNG deficiency
IFNG	Orphanet:805	Tuberous sclerosis complex
IFNG	Orphanet:88	Idiopathic aplastic anemia
SERPINC1	Orphanet:82	Hereditary thrombophilia due to congenital antithrombin deficiency
NTHL1	Orphanet:454840	NTHL1-related polyposis
PKD1	Orphanet:730	Autosomal dominant polycystic kidney disease
PKD1	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
PRKD1	Orphanet:276145	Malignant epithelial tumor of salivary glands
PRKD1	Orphanet:708019	Congenital heart defect-ectodermal dysplasia- brachydactyly-telangiectasia syndrome

Cohort genes → proteins

19 cohort genes, 17 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	19

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	gencc,clinvar
NHERF2	HGNC:11076	ENSG00000065054	Q15599	Na(+)/H(+) exchange regulatory cofactor NHE-RF2	clinvar
SYNGR3	HGNC:11501	ENSG00000127561	O43761	Synaptogyrin-3	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	clinvar
CRAMP1	HGNC:14122	ENSG00000007545	Q96RY5	Protein cramped-like	clinvar
ANTKMT	HGNC:14152	ENSG00000103254	Q9BQD7	Adenine nucleotide translocase lysine N-methyltransferase	clinvar
CCDC78	HGNC:14153	ENSG00000162004	A2IDD5	Coiled-coil domain-containing protein 78	clinvar
CASKIN1	HGNC:20879	ENSG00000167971	Q8WXD9	Caskin-1	clinvar
CFAP20DC	HGNC:24763	ENSG00000163689	Q6ZVT6	Protein CFAP20DC	clinvar
MIR1225	HGNC:33931	ENSG00000221656		microRNA 1225	clinvar
GFER	HGNC:4236	ENSG00000127554	P55789	FAD-linked sulfhydryl oxidase ALR	clinvar
IFNG	HGNC:5438	ENSG00000111537	P01579	Interferon gamma	clinvar
ECI1-AS1	HGNC:56088	ENSG00000261663		ECI1 antisense RNA 1	clinvar
SERPINC1	HGNC:775	ENSG00000117601	P01008	Antithrombin-III	clinvar
NTHL1	HGNC:8028	ENSG00000065057	P78549	Endonuclease III-like protein 1	clinvar
PKD1	HGNC:9008	ENSG00000008710	P98161	Polycystin-1	clinvar
PRKD1	HGNC:9407	ENSG00000184304	Q15139	Serine/threonine-protein kinase D1	clinvar
BAIAP3	HGNC:948	ENSG00000007516	O94812	BAI1-associated protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…
NHERF2	Na(+)/H(+) exchange regulatory cofactor NHE-RF2	Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression.
SYNGR3	Synaptogyrin-3	May play a role in regulated exocytosis.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
VHL	von Hippel-Lindau disease tumor suppressor	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
CRAMP1	Protein cramped-like	Transcription factor, which specifically drives expression of histone H1 genes.
ANTKMT	Adenine nucleotide translocase lysine N-methyltransferase	Mitochondrial protein-lysine N-methyltransferase that trimethylates adenine nucleotide translocases ANT2/SLC25A5 and ANT3/SLC25A6, thereby regulating mitochondrial respiration.
CCDC78	Coiled-coil domain-containing protein 78	Component of the deuterosome, a structure that promotes de novo centriole amplification in multiciliated cells that can generate more than 100 centrioles.
CASKIN1	Caskin-1	May link the scaffolding protein CASK to downstream intracellular effectors.
GFER	FAD-linked sulfhydryl oxidase ALR	FAD-dependent sulfhydryl oxidase that regenerates the redox-active disulfide bonds in CHCHD4/MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space.
IFNG	Interferon gamma	Type II interferon produced by immune cells such as T-cells and NK cells that plays crucial roles in antimicrobial, antiviral, and antitumor responses by activating effector immune cells and enhancing antigen presentation.
SERPINC1	Antithrombin-III	Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade.
NTHL1	Endonuclease III-like protein 1	Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage.
PKD1	Polycystin-1	Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B.
PRKD1	Serine/threonine-protein kinase D1	Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and tr…
BAIAP3	BAI1-associated protein 3	Functions in endosome to Golgi retrograde transport.

Protein-family classification

Druggable: 6 · Difficult: 2 · Unknown: 11 · Druggable fraction: 0.32

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	2	2.9×	0.503
Enzyme (other)	3	1.9×	0.503
Scaffold/PPI	2	1.8×	0.503
Antibody/Immunoglobulin	1	1.5×	0.523
Other/Unknown	11	1.0×	0.523

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
NHERF2	Scaffold/PPI	no		PDZ, EBP50_C, NHERF-1/NHERF-2
SYNGR3	Other/Unknown	no		Marvel, Synaptogyrin
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
VHL	Enzyme (other)	yes	2.3.2.B13	VHL_tumour_suppress_b/a_dom, VHL_alpha_dom, VHL_beta_dom
CRAMP1	Other/Unknown	no		SANT/Myb, SANT_dom, Cramped-like
ANTKMT	Other/Unknown	no		FAM173A/B, SAM-dependent_MTases_sf
CCDC78	Other/Unknown	no		DUF4472, CCDC78
CASKIN1	Scaffold/PPI	no		SH3_domain, SAM, Ankyrin_rpt
CFAP20DC	Other/Unknown	no		CFA20_dom, CFA20/CFAP20DC
MIR1225	Other/Unknown	no
GFER	Enzyme (other)	yes	1.8.3.2	ERV/ALR_sulphydryl_oxidase, ERV/ALR_sulphydryl_oxid_sf, ALR/ERV
IFNG	Other/Unknown	no		Interferon_gamma, 4_helix_cytokine-like_core
ECI1-AS1	Other/Unknown	no
SERPINC1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
NTHL1	Enzyme (other)	yes	4.2.99.18	HhH_motif, HhH-GPD_domain, Endonuclease3_FeS-loop_motif
PKD1	Antibody/Immunoglobulin	yes		GPS, LRRNT, PC1
PRKD1	Kinase	yes	2.7.11.13	Prot_kinase_dom, PH_domain, PKC_DAG/PE
BAIAP3	Other/Unknown	no		C2_dom, MUN_dom, Munc13_1

Expression context

Cohort genes with no expression data: 0.

16 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)	19
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	4
sural nerve	3
cerebellar cortex	2
cerebellar hemisphere	2
apex of heart	2
mucosa of transverse colon	2
right uterine tube	2
male germ line stem cell (sensu Vertebrata) in testis	2
right lobe of liver	2
metanephros cortex	1
right lung	1
Brodmann (1909) area 23	1
middle temporal gyrus	1
superior frontal gyrus	1
biceps brachii	1
gluteal muscle	1
skeletal muscle tissue of biceps brachii	1
cortical plate	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
NHERF2	179	ubiquitous	marker	apex of heart, right lung, metanephros cortex
SYNGR3	203	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, superior frontal gyrus
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
CRAMP1	242	ubiquitous	marker	thymus, sural nerve, right hemisphere of cerebellum
ANTKMT	243	ubiquitous	marker	anterior cingulate cortex, cingulate cortex, mucosa of transverse colon
CCDC78	176	broad	marker	right uterine tube, bronchial epithelial cell, bronchus
CASKIN1	170	broad	yes	right frontal lobe, right hemisphere of cerebellum, primary visual cortex
CFAP20DC	171	ubiquitous	marker	lower esophagus mucosa, left testis, right testis
MIR1225	77		yes	sural nerve, skeletal muscle tissue, Brodmann (1909) area 9
GFER	197	ubiquitous	marker	olfactory bulb, type B pancreatic cell, vena cava
IFNG	119	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, granulocyte, lymph node
ECI1-AS1	132		yes	primordial germ cell in gonad, sural nerve, male germ line stem cell (sensu Vertebrata) in testis
SERPINC1	153	tissue_specific	marker	right lobe of liver, liver, adrenal tissue
NTHL1	211	ubiquitous	marker	right lobe of liver, apex of heart, mucosa of transverse colon
PKD1	290		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PRKD1	239	ubiquitous	marker	ventricular zone, seminal vesicle, thoracic aorta
BAIAP3	203	broad	marker	right uterine tube, adenohypophysis, pituitary gland

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IFNG	7,383
TTN	4,237
TSC2	4,135
VHL	3,522
NHERF2	2,416
PRKD1	2,131
GFER	2,065
CASKIN1	2,015
NTHL1	1,994
SERPINC1	1,833

Intra-cohort edges

A	B	Sources
ANTKMT	CRAMP1	string_interaction
NHERF2	PRKD1	intact
PKD1	PRKD1	string_interaction
PKD1	TSC2	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 7 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VHL	P40337	142
TTN	Q8WZ42	64
SERPINC1	P01008	27
PKD1	P98161	13
IFNG	P01579	8
GFER	P55789	7
NHERF2	Q15599	4
CASKIN1	Q8WXD9	3
TSC2	P49815	2
NTHL1	P78549	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANTKMT	Q9BQD7	82.01
BAIAP3	O94812	81.27
SYNGR3	O43761	80.95
PRKD1	Q15139	68.99
CCDC78	A2IDD5	66.65
CFAP20DC	Q6ZVT6	53.59
CRAMP1	Q96RY5	50.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 46. Enrichment computed across 19 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective NTHL1 substrate processing	1	1268.9×	0.018	NTHL1
Defective NTHL1 substrate binding	1	1268.9×	0.018	NTHL1
R-HSA-140875	1	317.2×	0.029	SERPINC1
Replication of the SARS-CoV-1 genome	1	317.2×	0.029	VHL
Replication of the SARS-CoV-2 genome	1	317.2×	0.029	VHL
Inhibition of TSC complex formation by AKT (PKB)	1	253.8×	0.030	TSC2
R-HSA-140837	1	158.6×	0.032	SERPINC1
IFNG signaling activates MAPKs	1	158.6×	0.032	IFNG
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	1	126.9×	0.032	IFNG
RHOBTB3 ATPase cycle	1	126.9×	0.032	VHL
Displacement of DNA glycosylase by APEX1	1	115.3×	0.032	NTHL1
R-HSA-140877	1	105.7×	0.032	SERPINC1
Fibrin formation	1	97.6×	0.032	SERPINC1
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	1	97.6×	0.032	IFNG
AKT phosphorylates targets in the cytosol	1	90.6×	0.032	TSC2
Regulation of IFNG signaling	1	90.6×	0.032	IFNG
Amplification and propagation of coagulation cascade	1	70.5×	0.038	SERPINC1
VxPx cargo-targeting to cilium	1	57.7×	0.044	PKD1
Initiation of coagulation cascade	1	52.9×	0.045	SERPINC1
Constitutive Signaling by AKT1 E17K in Cancer	1	47.0×	0.048	TSC2
Energy dependent regulation of mTOR by LKB1-AMPK	1	43.8×	0.050	TSC2
Striated Muscle Contraction	1	34.3×	0.057	TTN
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	33.4×	0.057	IFNG
SUMOylation of ubiquitinylation proteins	1	32.5×	0.057	VHL
Sphingolipid de novo biosynthesis	1	31.7×	0.057	PRKD1
TBC/RABGAPs	1	28.8×	0.060	TSC2
Regulation of clotting cascade	1	25.9×	0.065	SERPINC1
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	1	21.9×	0.071	VHL
Protein localization	1	21.1×	0.071	GFER
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	20.5×	0.071	NTHL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of fructose 1,6-bisphosphate metabolic process	1	1053.2×	0.026	IFNG
metanephric distal tubule morphogenesis	1	1053.2×	0.026	PKD1
regulation of dense core granule exocytosis	1	1053.2×	0.026	BAIAP3
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	526.6×	0.026	PRKD1
obsolete positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation involved in immune response	1	526.6×	0.026	IFNG
positive regulation of peptidyl-serine phosphorylation of STAT protein	1	526.6×	0.026	IFNG
positive regulation of vitamin D biosynthetic process	1	526.6×	0.026	IFNG
nitrogen cycle metabolic process	1	526.6×	0.026	PKD1
mesonephric tubule development	1	526.6×	0.026	PKD1
positive regulation of iron ion import across plasma membrane	1	526.6×	0.026	IFNG
positive regulation of tumor necrosis factor (ligand) superfamily member 11 production	1	526.6×	0.026	IFNG
skeletal muscle myosin thick filament assembly	1	351.1×	0.026	TTN
positive regulation of transporter activity	1	351.1×	0.026	SYNGR3
lymph vessel morphogenesis	1	351.1×	0.026	PKD1
sarcomerogenesis	1	351.1×	0.026	TTN
regulation of neurotransmitter uptake	1	351.1×	0.026	SYNGR3
metanephric proximal tubule development	1	351.1×	0.026	PKD1
protein import into the intermembrane space via the disulfide relay system	1	351.1×	0.026	GFER
regulation of mitochondrial ATP synthesis coupled proton transport	1	351.1×	0.026	ANTKMT
dense core granule maturation	1	351.1×	0.026	BAIAP3
skeletal muscle contraction	2	63.8×	0.026	TTN, CCDC78
negative regulation of TORC1 signaling	2	40.5×	0.026	TSC2, VHL
cell surface receptor signaling pathway via JAK-STAT	2	36.3×	0.026	IFNG, PKD1
liver development	2	27.7×	0.026	GFER, PKD1
positive regulation of autophagy	2	26.0×	0.026	IFNG, PRKD1
calcium-independent cell-matrix adhesion	1	263.3×	0.031	PKD1
cellular response to norepinephrine stimulus	1	263.3×	0.031	PRKD1
metanephric ascending thin limb development	1	263.3×	0.031	PKD1
base-excision repair, AP site formation	1	210.7×	0.035	NTHL1
mesonephric duct development	1	210.7×	0.035	PKD1

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 15

Druggability breadth: 10 of 19 evidence-associated genes (53%) 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
VHL	OSIMERTINIB
GFER	FENOLDOPAM MESYLATE
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKD1	26	4
GFER	11	4
VHL	7	4
SERPINC1	1	3
TSC2	0	0
NHERF2	0	0
SYNGR3	0	0
TTN	0	0
CRAMP1	0	0
ANTKMT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OSIMERTINIB	4	VHL
BRIGATINIB	4	PRKD1, VHL
CRIZOTINIB	4	PRKD1, VHL
ADAGRASIB	4	VHL
FENOLDOPAM MESYLATE	4	GFER
PROMAZINE HYDROCHLORIDE	4	GFER
PROMETHAZINE HYDROCHLORIDE	4	GFER
PHENELZINE SULFATE	4	GFER
PYRITHIONE	4	GFER
DOPAMINE HYDROCHLORIDE	4	GFER
MEPAZINE ACETATE	4	GFER
CHLORPROMAZINE HYDROCHLORIDE	4	GFER
OLANZAPINE	4	GFER
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
GEFITINIB	4	PRKD1
RESVERATROL	3	GFER
IDRAPARINUX SODIUM	3	SERPINC1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
ZIMLOVISERTIB	2	VHL
FORETINIB	2	VHL
PTEROSTILBENE	2	GFER
PHORBOL MYRISTATE ACETATE	2	PRKD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39
PRKD1	660	Binding:650, Functional:10
PKD1	27	Binding:27
SERPINC1	19	Binding:19
NTHL1	8	Binding:7, Functional:1
NHERF2	2	Binding:2
TSC2	1	Binding:1
TTN	1	Binding:1
GFER	1	Binding:1
IFNG	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase
VHL	2.3.2.B13
GFER	1.8.3.2	thiol oxidase
NTHL1	4.2.99.18	DNA-(apurinic or apyrimidinic site) lyase
PRKD1	2.7.11.13	protein kinase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
VHL	3,575
PRKD1	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 18; 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)
OSIMERTINIB	4	VHL
BRIGATINIB	4	PRKD1, VHL
CRIZOTINIB	4	PRKD1, VHL
ADAGRASIB	4	VHL
FENOLDOPAM MESYLATE	4	GFER
PROMAZINE HYDROCHLORIDE	4	GFER
PROMETHAZINE HYDROCHLORIDE	4	GFER
PHENELZINE SULFATE	4	GFER
PYRITHIONE	4	GFER
DOPAMINE HYDROCHLORIDE	4	GFER
MEPAZINE ACETATE	4	GFER
CHLORPROMAZINE HYDROCHLORIDE	4	GFER
OLANZAPINE	4	GFER
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
GEFITINIB	4	PRKD1
RESVERATROL	3	GFER
IDRAPARINUX SODIUM	3	SERPINC1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
ZIMLOVISERTIB	2	VHL
FORETINIB	2	VHL
PTEROSTILBENE	2	GFER
PHORBOL MYRISTATE ACETATE	2	PRKD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	VHL, GFER, PRKD1
B	Phased (≥1) drug, not yet approved	1	SERPINC1
C	Druggable family + PDB, no drug	3	TTN, NTHL1, PKD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	12	TSC2, NHERF2, SYNGR3, CRAMP1, ANTKMT, CCDC78, CASKIN1, CFAP20DC, MIR1225, IFNG (+2 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PKD1	27	PRKD1
TSC2	1	—
NHERF2	2	—
SYNGR3	0	—
TTN	1	—
CRAMP1	0	—
ANTKMT	0	—
CCDC78	0	—
CASKIN1	0	—
CFAP20DC	0	—
MIR1225	0	—
IFNG	1	—
ECI1-AS1	0	—
NTHL1	8	—
BAIAP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05103358	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)
NCT02201212	PHASE2	COMPLETED	Everolimus for Cancer With TSC1 or TSC2 Mutation
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03817515	Not specified	APPROVED_FOR_MARKETING	Expanded Access for ABI-009 in Patients With Advanced PEComa and Patients With a Malignancy With Relevant Genetic Mutations or mTOR Pathway Activation

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EVEROLIMUS	4	1