Tuberous sclerosis

Summary

Tuberous sclerosis (MONDO:0001734) is a disease with 6 cohort genes and 95 clinical trials. Molecularly, TSC1 Loss-of-function confers sensitivity to Everolimus in Tuberous Sclerosis (CIViC Level A); 2 further subtype–drug associations are mapped below. Top therapeutic interventions include cannabidiol, doxycycline anhydrous, and ganaxolone.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 6
• ClinVar variants: 5,015
• Phenotypes (HPO): 62
• Clinical trials: 95
• Precision-medicine evidence (CIViC): 3 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

6 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Worldwide	Validated
Point prevalence	1-9 / 100 000	1.58	Taiwan, Province of China	Validated
Point prevalence	1-9 / 100 000	3.87	Hong Kong	Validated
Point prevalence	1-9 / 100 000	5.38	Sweden	Validated
Prevalence at birth	1-9 / 100 000	5.62	Germany	Validated
Prevalence at birth	1-9 / 100 000	4.45	United Kingdom	Validated

Signs & symptoms

Clinical features (HPO)

62 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000077	Abnormality of the kidney	Very frequent (80-99%)
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0002539	Cortical dysplasia	Very frequent (80-99%)
HP:0009716	Subependymal nodules	Very frequent (80-99%)
HP:0009717	Cortical tubers	Very frequent (80-99%)
HP:0009719	Hypomelanotic macule	Very frequent (80-99%)
HP:0011354	Generalized abnormality of skin	Very frequent (80-99%)
HP:0000107	Renal cyst	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000717	Autism	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000752	Hyperactivity	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0002133	Status epilepticus	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0007359	Focal-onset seizure	Frequent (30-79%)
HP:0007449	Confetti-like hypopigmented macules	Frequent (30-79%)
HP:0008762	Repetitive compulsive behavior	Frequent (30-79%)
HP:0009594	Retinal hamartoma	Frequent (30-79%)
HP:0009721	Shagreen patch	Frequent (30-79%)
HP:0009729	Cardiac rhabdomyoma	Frequent (30-79%)
HP:0010615	Angiofibromas	Frequent (30-79%)
HP:0011097	Epileptic spasm	Frequent (30-79%)
HP:0012433	Abnormal social behavior	Frequent (30-79%)
HP:0012469	Infantile spasms	Frequent (30-79%)
HP:0012622	Chronic kidney disease	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0012798	Pulmonary lymphangiomyomatosis	Frequent (30-79%)
HP:0040030	Chorioretinal hypopigmentation	Frequent (30-79%)
HP:0100710	Impulsivity	Frequent (30-79%)
HP:0100716	Self-injurious behavior	Frequent (30-79%)
HP:0200035	Skin plaque	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0001407	Hepatic cysts	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002105	Hemoptysis	Occasional (5-29%)
HP:0002465	Poor speech	Occasional (5-29%)
HP:0006772	Renal angiomyolipoma	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0009718	Subependymal giant-cell astrocytoma	Occasional (5-29%)
HP:0010953	Noncommunicating hydrocephalus	Occasional (5-29%)
HP:0011947	Respiratory tract infection	Occasional (5-29%)
HP:0100804	Ungual fibroma	Occasional (5-29%)
HP:0200040	Epidermoid cyst	Occasional (5-29%)
HP:0000113	Polycystic kidney dysplasia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	tuberous sclerosis
Mondo ID	MONDO:0001734
MeSH	D014402
OMIM	191100
Orphanet	805
DOID	DOID:13515
ICD-10-CM	Q85.1
ICD-11	1903085809
NCIT	C3424
SNOMED CT	7199000
UMLS	C0041341
MedGen	22518
GARD	0007830
MedDRA	10045138
NORD	1802
Is cancer (heuristic)	no

Also known as: adenoma sebaceum · adenoma sebaceum syndrome · Bourneville disease · Bourneville syndrome · Bourneville’s disease · Bourneville’s syndrome · epiloia · TSC · tuberous sclerosis · tuberous sclerosis complex · tuberous sclerosis syndrome

Data availability: 5,015 ClinVar variants · 82 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (2): tuberous sclerosis 1, tuberous sclerosis 2

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:

182 uncertain significance, 159 conflicting classifications of pathogenicity, 148 benign/likely benign, 87 likely benign, 17 pathogenic, 5 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1415522	NM_000368.5(TSC1):c.1412del (p.Asp471fs)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1433287	NM_000368.5(TSC1):c.1192del (p.Ala398fs)	TSC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1796488	NM_000368.5(TSC1):c.2824C>T (p.Gln942Ter)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1953076	NM_000368.5(TSC1):c.1257dup (p.Arg420fs)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
12392	NM_000548.5(TSC2):c.4642del (p.Leu1548fs)	TSC2	Pathogenic	no assertion criteria provided
12393	NM_000548.5(TSC2):c.5024C>T (p.Pro1675Leu)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12394	NM_000548.5(TSC2):c.34A>T (p.Lys12Ter)	TSC2	Pathogenic	no assertion criteria provided
12395	NM_000548.5(TSC2):c.2056_2059dup (p.Ser687fs)	TSC2	Pathogenic	no assertion criteria provided
12396	NM_000548.5(TSC2):c.1513C>T (p.Arg505Ter)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12397	NM_000548.5(TSC2):c.1832G>A (p.Arg611Gln)	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12398	NM_000548.5(TSC2):c.2150T>G (p.Leu717Arg)	TSC2	Pathogenic	no assertion criteria provided
12399	NM_000548.5(TSC2):c.1432C>T (p.Gln478Ter)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12400	NM_000548.5(TSC2):c.1096G>T (p.Glu366Ter)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12401	NM_000548.5(TSC2):c.4508A>C (p.Gln1503Pro)	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12402	NM_000548.5(TSC2):c.5238_5255del (p.His1746_Arg1751del)	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12403	NM_000548.5(TSC2):c.2714G>A (p.Arg905Gln)	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12404	NM_000548.5(TSC2):c.2713C>T (p.Arg905Trp)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12405	NM_000548.5(TSC2):c.2713C>G (p.Arg905Gly)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12406	NM_000548.5(TSC2):c.2355+2_2355+5del	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12407	NM_000548.5(TSC2):c.1322G>A (p.Trp441Ter)	TSC2	Pathogenic	criteria provided, single submitter
1696844	NM_000548.5(TSC2):c.1327C>T (p.Gln443Ter)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1753871	NM_000548.5(TSC2):c.1224del (p.Phe408fs)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
185096	NM_001042492.3(NF1):c.3686A>G (p.Asn1229Ser)	NF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000487	NM_000368.5(TSC1):c.1015A>T (p.Thr339Ser)	TSC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1004712	NM_000368.5(TSC1):c.720T>G (p.His240Gln)	TSC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1018339	NM_000368.5(TSC1):c.771C>A (p.Ile257=)	TSC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1023970	NM_000368.5(TSC1):c.1193C>T (p.Ala398Val)	TSC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024630	NM_000368.5(TSC1):c.2984G>A (p.Cys995Tyr)	TSC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1026309	NM_000368.5(TSC1):c.542A>T (p.His181Leu)	TSC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1046012	NM_000368.5(TSC1):c.364A>G (p.Met122Val)	TSC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 24 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSC1	Orphanet:210159	Adult hepatocellular carcinoma
TSC1	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC1	Orphanet:538	Lymphangioleiomyomatosis
TSC1	Orphanet:805	Tuberous sclerosis complex
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
ROBO3	Orphanet:2744	Horizontal gaze palsy with progressive scoliosis
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma
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

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSC1	HGNC:12362	ENSG00000165699	Q92574	Hamartin	clinvar,civic_evidence
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
ROBO3	HGNC:13433	ENSG00000154134	Q96MS0	Roundabout homolog 3	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar
PKD1	HGNC:9008	ENSG00000008710	P98161	Polycystin-1	clinvar
PRKD1	HGNC:9407	ENSG00000184304	Q15139	Serine/threonine-protein kinase D1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSC1	Hamartin	Non-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 macromolec…
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…
ROBO3	Roundabout homolog 3	Receptor involved in axon guidance during development.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
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…

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	2	9.7×	0.048
Kinase	1	4.6×	0.297
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSC1	Other/Unknown	no		Hamartin
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
ROBO3	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
PKD1	Antibody/Immunoglobulin	yes		GPS, LRRNT, PC1
PRKD1	Kinase	yes	2.7.11.13	Prot_kinase_dom, PH_domain, PKC_DAG/PE

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
gluteal muscle	1
lateral globus pallidus	1
substantia nigra pars compacta	1
left ovary	1
right ovary	1
right uterine tube	1
adrenal tissue	1
calcaneal tendon	1
colonic epithelium	1
seminal vesicle	1
thoracic aorta	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSC1	297	ubiquitous	marker	substantia nigra pars compacta, gluteal muscle, lateral globus pallidus
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ROBO3	238	ubiquitous	marker	right uterine tube, left ovary, right ovary
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
PKD1	290		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PRKD1	239	ubiquitous	marker	ventricular zone, seminal vesicle, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NF1	5,540
TSC1	5,445
TSC2	4,135
PRKD1	2,131
ROBO3	1,382
PKD1	1,370

Intra-cohort edges

A	B	Sources
PKD1	PRKD1	string_interaction
PKD1	TSC1	string_interaction
PKD1	TSC2	string_interaction
TSC1	TSC2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NF1	P21359	26
PKD1	P98161	13
TSC1	Q92574	5
ROBO3	Q96MS0	3
TSC2	P49815	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRKD1	Q15139	68.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Inhibition of TSC complex formation by AKT (PKB)	2	761.3×	6e-05	TSC1, TSC2
Energy dependent regulation of mTOR by LKB1-AMPK	2	131.3×	0.001	TSC1, TSC2
TBC/RABGAPs	2	86.5×	0.002	TSC1, TSC2
TP53 Regulates Metabolic Genes	2	43.3×	0.005	TSC1, TSC2
Macroautophagy	2	38.5×	0.005	TSC1, TSC2
RAS signaling downstream of NF1 loss-of-function variants	1	271.9×	0.015	NF1
ROBO receptors bind AKAP5	1	211.5×	0.016	ROBO3
Regulation of commissural axon pathfinding by SLIT and ROBO	1	158.6×	0.019	ROBO3
AKT phosphorylates targets in the cytosol	1	135.9×	0.020	TSC2
VxPx cargo-targeting to cilium	1	86.5×	0.028	PKD1
Constitutive Signaling by AKT1 E17K in Cancer	1	70.5×	0.031	TSC2
Sphingolipid de novo biosynthesis	1	47.6×	0.042	PRKD1
Oncogenic MAPK signaling	1	41.4×	0.044	NF1
Regulation of RAS by GAPs	1	32.3×	0.052	NF1
Sphingolipid metabolism	1	28.0×	0.056	PRKD1
MAPK1/MAPK3 signaling	1	21.9×	0.067	NF1
MAPK family signaling cascades	1	17.1×	0.080	NF1
Regulation of expression of SLITs and ROBOs	1	11.5×	0.112	ROBO3
RAF/MAP kinase cascade	1	10.2×	0.119	NF1
Diseases of signal transduction by growth factor receptors and second messengers	1	9.5×	0.121	NF1
Metabolism of lipids	1	5.3×	0.201	PRKD1
Disease	1	2.2×	0.414	NF1
Metabolism	1	1.9×	0.436	PRKD1
Signal Transduction	1	1.7×	0.463	NF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of cell-matrix adhesion	2	432.1×	0.002	TSC1, NF1
negative regulation of TOR signaling	2	187.2×	0.002	TSC1, TSC2
neural tube development	2	175.5×	0.002	NF1, PKD1
spinal cord development	2	170.2×	0.002	NF1, PKD1
heart development	3	39.4×	0.002	TSC2, NF1, PKD1
regulation of cell cycle	3	37.3×	0.002	TSC1, TSC2, PKD1
negative regulation of TORC1 signaling	2	108.0×	0.005	TSC1, TSC2
positive regulation of mast cell apoptotic process	1	2808.7×	0.006	NF1
regulation of glial cell differentiation	1	2808.7×	0.006	NF1
metanephric distal tubule morphogenesis	1	2808.7×	0.006	PKD1
observational learning	1	2808.7×	0.006	NF1
positive regulation of endothelial cell proliferation	2	77.0×	0.006	NF1, PRKD1
liver development	2	73.9×	0.006	NF1, PKD1
cerebral cortex development	2	68.5×	0.006	TSC1, NF1
cellular response to starvation	2	64.6×	0.006	TSC1, TSC2
neural tube closure	2	62.4×	0.006	TSC1, TSC2
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	1404.3×	0.007	PRKD1
gamma-aminobutyric acid secretion, neurotransmission	1	1404.3×	0.007	NF1
nitrogen cycle metabolic process	1	1404.3×	0.007	PKD1
mesonephric tubule development	1	1404.3×	0.007	PKD1
positive regulation of axon guidance	1	1404.3×	0.007	ROBO3
cell-matrix adhesion	2	54.5×	0.007	TSC1, PKD1
protein import into nucleus	2	48.0×	0.007	TSC2, NF1
kidney development	2	46.8×	0.007	TSC1, PKD1
homophilic cell-cell adhesion	2	46.8×	0.007	ROBO3, PKD1
Schwann cell proliferation	1	936.2×	0.007	NF1
forebrain astrocyte development	1	936.2×	0.007	NF1
Schwann cell migration	1	936.2×	0.007	NF1
lymph vessel morphogenesis	1	936.2×	0.007	PKD1
memory T cell differentiation	1	936.2×	0.007	TSC1

Therapeutics

Drugs indicated for this disease

2 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Everolimus	Approved (phase 4)
Sirolimus	Approved (phase 4)
Ganaxolone	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Vigabatrin.

Drug target analysis

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

Druggability breadth: 3 of 6 evidence-associated genes (50%) 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
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKD1	26	4
TSC1	0	0
TSC2	0	0
ROBO3	0	0
NF1	0	0
PKD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRKD1	660	Binding:650, Functional:10
PKD1	27	Binding:27
TSC2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
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
PRKD1	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

26 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)
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	ROBO3, PKD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TSC1, TSC2, NF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PKD1	27	PRKD1
TSC1	0	—
TSC2	1	—
ROBO3	0	—
NF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 95.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	47
PHASE2	18
PHASE3	12
PHASE1/PHASE2	9
PHASE1	4
PHASE2/PHASE3	3
PHASE4	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05044819	PHASE4	ACTIVE_NOT_RECRUITING	Assessment of Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution
NCT00989742	PHASE4	COMPLETED	Doxycycline In Lymphangioleiomyomatosis (LAM)
NCT02962414	PHASE3	ACTIVE_NOT_RECRUITING	Roll-over Study to Collect and Assess Long-term Safety of Everolimus in Patients With TSC and Refractory Seizures Who Have Completed the EXIST-3 Study [CRAD001M2304] and Who Are Benefitting From Continued Treatment
NCT05534672	PHASE3	RECRUITING	Placebo Controlled Study to Assess the Efficacy and Safety of Rapamycin in Drug Resistant Epilepsy Associated With Tuberous Sclerosis Complex
NCT07403266	PHASE3	RECRUITING	Treatment With Full-spectrum Cannabis Extract of Refractory Epilepsy Associated With Tuberous Sclerosis Complex (TSC)
NCT00789828	PHASE3	COMPLETED	Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC)(EXIST-1)
NCT00790400	PHASE3	COMPLETED	Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
NCT01730209	PHASE2/PHASE3	UNKNOWN	Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex
NCT02544750	PHASE3	COMPLETED	An Open-label Extension Trial of Cannabidiol (GWP42003-P, CBD) for Seizures in Tuberous Sclerosis Complex (GWPCARE6)
NCT02544763	PHASE3	COMPLETED	A Randomized Controlled Trial of Cannabidiol (GWP42003-P, CBD) for Seizures in Tuberous Sclerosis Complex (GWPCARE6)
NCT02634931	PHASE3	COMPLETED	Long-term Trial of Topical Sirolimus to Angiofibroma in Patient With Tuberous Sclerosis Complex
NCT02635789	PHASE3	COMPLETED	Phase III Trial of Topical Formulation of Sirolimus to Skin Lesions in Patients With Tuberous Sclerosis Complex (TSC)
NCT03826628	PHASE2/PHASE3	COMPLETED	Dose-Ranging Efficacy and Safety Study of Topical Rapamycin Cream for Facial Angiofibroma Associated With Tuberous Sclerosis Complex
NCT04987463	PHASE2/PHASE3	UNKNOWN	Efficacy and Safety of Rapamycin Versus Vigabatrin in the Prevention of Tuberous Sclerosis Complex Symptoms in Infants
NCT05323734	PHASE3	COMPLETED	Adjunctive GNX Treatment Compared With Placebo in Children and Adults With TSC-related Epilepsy
NCT05495425	PHASE3	COMPLETED	Clinical Study of NPC-12Y Gel in Patients With Skin Lesions Associated With TSC
NCT05604170	PHASE3	TERMINATED	Open-label Study of Adjunctive GNX Treatment in Children and Adults With TSC-related Epilepsy
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)
NCT05104983	PHASE2	RECRUITING	Stopping TSC Onset and Progression 2B: Sirolimus TSC Epilepsy Prevention Study
NCT05467397	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Feasibility of [11C]Acetate-PET in LAM and TSC
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06392009	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Astroscape: A Study of Radiprodil on Safety, Tolerability, Pharmacokinetics, and Effect on Seizures and Behavioral Symptoms in Patients With TSC or FCD Type II
NCT07287202	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety, Tolerability, and Pharmacokinetics of SVG103 (Paxalisib) in Focal Cortical Dysplasia Type II (FCD-II), Tuberous Sclerosis Complex (TSC) or Hemimegalencephaly (HME)
NCT00126672	PHASE2	COMPLETED	RAPAMYCIN FOR KIDNEY ANGIOMYOLIPOMAS
NCT00411619	PHASE1/PHASE2	COMPLETED	Everolimus (RAD001) Therapy of Giant Cell Astrocytoma in Patients With Tuberous Sclerosis Complex
NCT00457808	PHASE2	COMPLETED	Rapamycin Therapy for Patients With Tuberous Sclerosis Complex and Sporadic LAM
NCT00457964	PHASE1/PHASE2	COMPLETED	RAD001 Therapy of Angiomyolipomata in Patients With TS Complex and Sporadic LAM
NCT00490789	PHASE2	UNKNOWN	Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM
NCT00792766	PHASE1/PHASE2	COMPLETED	Long Term Follow Up for RAD001 Therapy of Angiomyolipomata in Patients With Tuberous Sclerosis (TSC) and Sporadic Lymphangioleiomyomatosis (LAM)
NCT01070316	PHASE1/PHASE2	COMPLETED	Everolimus (RAD001) Therapy for Epilepsy in Patients With Tuberous Sclerosis Complex (TSC)
NCT01289912	PHASE2	COMPLETED	Trial of RAD001 and Neurocognition in Tuberous Sclerosis Complex (TSC)
NCT01526356	PHASE2	COMPLETED	Topical Rapamycin to Erase Angiofibromas in TSC
NCT01929642	PHASE2	COMPLETED	Rapalogues for Autism Phenotype in TSC: A Feasibility Study
NCT01954693	PHASE2	UNKNOWN	A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis
NCT02061397	PHASE1/PHASE2	COMPLETED	Safety of Simvastatin in LAM and TSC
NCT02104011	PHASE2	COMPLETED	Treatment of Renal Angiomyolipomas in Tuberous Sclerosis by Beta-blockers
NCT02201212	PHASE2	COMPLETED	Everolimus for Cancer With TSC1 or TSC2 Mutation
NCT02451696	PHASE2	COMPLETED	A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD
NCT02849457	PHASE2	COMPLETED	Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex
NCT03356769	PHASE2	UNKNOWN	Aspirin as an add-on Treatment of Refractory Epilepsy in Tuberous Sclerosis Complex

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CANNABIDIOL	4	3
DOXYCYCLINE ANHYDROUS	4	3
GANAXOLONE	4	3
VIGABATRIN	4	2
RADIPRODIL	2	2
CHEMBL4079877	0	1
CHEMBL4525833	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 3 predictive associations from 3 curated evidence items; also 2 predisposing.

Molecular subtype	Therapy	Effect	Level	CIViC
TSC1 Loss-of-function	Everolimus	Sensitivity/Response	CIViC A	EID7280
TSC1 mutation OR TSC2 mutation	Everolimus	Sensitivity/Response	CIViC A	EID11269
TSC2 Loss-of-function	Everolimus	Sensitivity/Response	CIViC A	EID7281