Tuberous sclerosis 1

Summary

Tuberous sclerosis 1 (MONDO:0008612) is a disease caused by TSC1 (GenCC Definitive), with 10 cohort genes and 4 clinical trials. Top therapeutic interventions include everolimus.

At a glance

• Causal gene: TSC1 (GenCC Definitive)
• Cohort genes: 10
• ClinVar variants: 4,390
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	tuberous sclerosis 1
Mondo ID	MONDO:0008612
MeSH	C565346
OMIM	191100
DOID	DOID:0080324
NCIT	C75122
UMLS	C1854465
MedGen	344288
GARD	0015121
Is cancer (heuristic)	no

Also known as: TSC1 · TSC1 tuberous sclerosis · TSC1-related tuberous sclerosis · tuberous sclerosis 1 · tuberous sclerosis caused by mutation in TSC1 · tuberous sclerosis type 1 · tuberous sclerosis, type 1 · tuberous sclerosis-1

Data availability: 4,390 ClinVar variants · 4 GenCC gene-disease records · 26 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 1

Related subtypes (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:

291 uncertain significance, 114 likely benign, 74 benign/likely benign, 62 conflicting classifications of pathogenicity, 50 pathogenic, 3 likely pathogenic, 3 benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064009	NC_000009.11:g.(?135777972)(135782777_?)del	TSC1	Pathogenic	criteria provided, single submitter
1066806	NM_000368.5(TSC1):c.1997+2T>G	TSC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068682	NM_000368.5(TSC1):c.2547del (p.Asn849fs)	TSC1	Pathogenic	criteria provided, single submitter
1068699	NM_000368.5(TSC1):c.398dup (p.Val135fs)	TSC1	Pathogenic	criteria provided, single submitter
1069083	NM_000368.5(TSC1):c.2130dup (p.Gln711fs)	TSC1	Pathogenic	criteria provided, single submitter
1069326	NM_000368.5(TSC1):c.1201del (p.Cys401fs)	TSC1	Pathogenic	criteria provided, single submitter
1069584	NM_000368.5(TSC1):c.561_562dup (p.Phe188fs)	TSC1	Pathogenic	criteria provided, single submitter
1069661	NM_000368.5(TSC1):c.1797del (p.Gln600fs)	TSC1	Pathogenic	criteria provided, single submitter
1070472	NM_000368.5(TSC1):c.343del (p.Ser115fs)	TSC1	Pathogenic	criteria provided, single submitter
1071239	NM_000368.5(TSC1):c.344del (p.Ser115fs)	TSC1	Pathogenic	criteria provided, single submitter
1071252	NM_000368.5(TSC1):c.913+1G>T	TSC1	Pathogenic	criteria provided, single submitter
1071660	NM_000368.5(TSC1):c.1873_1876dup (p.Glu626fs)	TSC1	Pathogenic	criteria provided, single submitter
1071787	NM_000368.5(TSC1):c.526dup (p.Tyr176fs)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1071872	NM_000368.5(TSC1):c.397_406del (p.Gly132_Val133insTer)	TSC1	Pathogenic	criteria provided, single submitter
1072063	NM_000368.5(TSC1):c.393_405del (p.Thr131_Gly132insTer)	TSC1	Pathogenic	criteria provided, single submitter
1072658	NM_000368.5(TSC1):c.2599C>T (p.Gln867Ter)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1072813	NM_000368.5(TSC1):c.17del (p.Asn6fs)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073148	NM_000368.5(TSC1):c.2065dup (p.Arg689fs)	TSC1	Pathogenic	criteria provided, single submitter
1073268	NM_000368.5(TSC1):c.1898del (p.Gly633fs)	TSC1	Pathogenic	criteria provided, single submitter
1073328	NM_000368.5(TSC1):c.2771_2772insTTTTTATTTTTTATTTTTTTTTTTTTTATTTTTTTTTTAAAGGTAACATTCATCAGTAGCGCAGGTTGTTTTTGTATTGGGGGGTAAATCCTCAAGTCAAGCTCGACAGAANNNNNNNNNNTCTCGCTCTCGTGTCCTCGGTAGACGCCGTGTTGGGCCTCCCACAGTGCTGGGATTACTGGCGTGCGCCAGCGCGCCCGGCCGAAAGACCACCTTCTTTT (p.Leu924delinsPhePheTyrPheLeuPhePhePhePheLeuPhePhePheTer)	TSC1	Pathogenic	criteria provided, single submitter
1073516	NM_000368.5(TSC1):c.945dup (p.Arg316fs)	TSC1	Pathogenic	criteria provided, single submitter
1073564	NM_000368.5(TSC1):c.181dup (p.Leu61fs)	TSC1	Pathogenic	criteria provided, single submitter
1074020	NM_000368.5(TSC1):c.1285_1298del (p.Arg429fs)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074231	NM_000368.5(TSC1):c.181del (p.Ile60_Leu61insTer)	TSC1	Pathogenic	criteria provided, single submitter
1075152	NM_000368.5(TSC1):c.2141del (p.Leu714fs)	TSC1	Pathogenic	criteria provided, single submitter
1075215	NC_000009.11:g.(?135771622)(135820530_?)del	TSC1	Pathogenic	criteria provided, single submitter
1075216	NC_000009.11:g.(?135782098)(135796843_?)del	TSC1	Pathogenic	criteria provided, single submitter
1076275	NM_000368.5(TSC1):c.1027C>T (p.Gln343Ter)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076403	NM_000368.5(TSC1):c.1450A>T (p.Arg484Ter)	TSC1	Pathogenic	criteria provided, single submitter
1076667	NM_000368.5(TSC1):c.2212_2213dup (p.Asp738fs)	TSC1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 16 · 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
TSC1	Definitive	Autosomal dominant	tuberous sclerosis 1	6

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
CEL	Orphanet:552	MODY
GFI1B	Orphanet:140957	Autosomal dominant macrothrombocytopenia
GFI1B	Orphanet:734	Alpha delta granule deficiency
PI4KA	Orphanet:436252	Combined immunodeficiency-multiple intestinal atresia
PI4KA	Orphanet:631079	Autosomal recessive spastic paraplegia type 84
PI4KA	Orphanet:98889	Bilateral perisylvian polymicrogyria

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSC1	HGNC:12362	ENSG00000165699	Q92574	Hamartin	gencc,clinvar
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
VAV2	HGNC:12658	ENSG00000160293	P52735	Guanine nucleotide exchange factor VAV2	clinvar
CEL	HGNC:1848	ENSG00000170835	P19835	Bile salt-activated lipase	clinvar
GBGT1	HGNC:20460	ENSG00000148288	Q8N5D6	Globoside alpha-1,3-N-acetylgalactosaminyltransferase 1	clinvar
AK8	HGNC:26526	ENSG00000165695	Q96MA6	Adenylate kinase 8	clinvar
GFI1B	HGNC:4238	ENSG00000165702	Q5VTD9	Zinc finger protein Gfi-1b	clinvar
GTF3C5	HGNC:4668	ENSG00000148308	Q9Y5Q8	General transcription factor 3C polypeptide 5	clinvar
ABO	HGNC:79	ENSG00000175164	P16442	Histo-blood group ABO system transferase	clinvar
PI4KA	HGNC:8983	ENSG00000241973	P42356	Phosphatidylinositol 4-kinase alpha	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…
VAV2	Guanine nucleotide exchange factor VAV2	Guanine nucleotide exchange factor for the Rho family of Ras-related GTPases.
CEL	Bile salt-activated lipase	Catalyzes the hydrolysis of a wide range of substrates including cholesteryl esters, phospholipids, lysophospholipids, di- and tri-acylglycerols, and fatty acid esters of hydroxy fatty acids (FAHFAs).
GBGT1	Globoside alpha-1,3-N-acetylgalactosaminyltransferase 1	Has lost the ability to synthesize Forssman glycolipid antigen (FORS1/FG).
AK8	Adenylate kinase 8	Nucleoside monophosphate (NMP) kinase that catalyzes the reversible transfer of the terminal phosphate group between nucleoside triphosphates and monophosphates.
GFI1B	Zinc finger protein Gfi-1b	Essential proto-oncogenic transcriptional regulator necessary for development and differentiation of erythroid and megakaryocytic lineages.
GTF3C5	General transcription factor 3C polypeptide 5	Involved in RNA polymerase III-mediated transcription.
ABO	Histo-blood group ABO system transferase	This protein is the basis of the ABO blood group system.
PI4KA	Phosphatidylinositol 4-kinase alpha	Acts on phosphatidylinositol (PtdIns) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate.

Protein-family classification

Druggable: 5 · Difficult: 3 · Unknown: 2 · 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
Enzyme (other)	4	4.8×	0.034
Kinase	1	2.8×	0.561
Scaffold/PPI	1	1.7×	0.561
Transcription factor	2	1.6×	0.561
Other/Unknown	2	0.4×	0.996

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
VAV2	Scaffold/PPI	no		DH_dom, SH2, GDS_CDC24_CS
CEL	Enzyme (other)	yes	3.1.1.13	CarbesteraseB, Carboxylesterase_B_CS, Carboxylesterase_B_AS
GBGT1	Enzyme (other)	yes	2.4.1.88	Glyco_trans_6, Nucleotide-diphossugar_trans
AK8	Enzyme (other)	yes	2.7.4.3	Adenylat/UMP-CMP_kin, P-loop_NTPase, ADK_active_lid_dom_sf
GFI1B	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
GTF3C5	Transcription factor	no		TF_IIIC_su-5_HTH, TF_IIIC_Tfc1/Sfc1, Tfc1/Sfc1_N
ABO	Enzyme (other)	yes	2.4.1.37	Glyco_trans_6, Nucleotide-diphossugar_trans
PI4KA	Kinase	yes		PI3/4_kinase_cat_dom, PI3K_accessory_dom, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

10 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
monocyte	2
gluteal muscle	1
lateral globus pallidus	1
substantia nigra pars compacta	1
ganglionic eminence	1
parotid gland	1
ventricular zone	1
body of pancreas	1
pancreas	1
type B pancreatic cell	1
body of stomach	1
leukocyte	1
cardiac muscle of right atrium	1
kidney epithelium	1
right uterine tube	1
sperm	1
trabecular bone tissue	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
VAV2	248	ubiquitous	marker	parotid gland, ganglionic eminence, ventricular zone
CEL	186	tissue_specific	marker	body of pancreas, type B pancreatic cell, pancreas
GBGT1	208	ubiquitous	marker	body of stomach, monocyte, leukocyte
AK8	166	broad	marker	right uterine tube, cardiac muscle of right atrium, kidney epithelium
GFI1B	126	tissue_specific	marker	sperm, trabecular bone tissue, monocyte
GTF3C5	252	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ABO	169	broad	marker	tendon of biceps brachii, buccal mucosa cell, right lobe of thyroid gland
PI4KA	143	ubiquitous	marker	superior frontal gyrus, right frontal lobe, Brodmann (1909) area 9

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSC1	5,445
TSC2	4,135
AK8	2,862
GTF3C5	1,933
PI4KA	1,755
VAV2	1,746
GFI1B	1,554
CEL	1,233
GBGT1	483
ABO	227

Intra-cohort edges

A	B	Sources
TSC1	TSC2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 7 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABO	P16442	151
VAV2	P52735	7
CEL	P19835	7
TSC1	Q92574	5
PI4KA	P42356	4
TSC2	P49815	2
GTF3C5	Q9Y5Q8	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AK8	Q96MA6	87.47
GBGT1	Q8N5D6	86.39
GFI1B	Q5VTD9	64.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 46. Enrichment computed across 10 evidence-associated genes (7 with Reactome annotation).

Pathways by enrichment

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

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Inhibition of TSC complex formation by AKT (PKB)	2	652.6×	1e-04	TSC1, TSC2
Energy dependent regulation of mTOR by LKB1-AMPK	2	112.5×	0.003	TSC1, TSC2
TBC/RABGAPs	2	74.2×	0.005	TSC1, TSC2
TP53 Regulates Metabolic Genes	2	37.1×	0.014	TSC1, TSC2
Macroautophagy	2	33.0×	0.014	TSC1, TSC2
Synthesis of PIPs at the ER membrane	1	326.3×	0.023	PI4KA
Digestion of dietary lipid	1	233.1×	0.028	CEL
AKT phosphorylates targets in the cytosol	1	116.5×	0.039	TSC2
Digestion and absorption	1	108.8×	0.039	CEL
Synthesis of PIPs at the Golgi membrane	1	90.6×	0.039	PI4KA
Digestion	1	81.6×	0.039	CEL
Signal transduction by L1	1	74.2×	0.039	VAV2
Azathioprine ADME	1	70.9×	0.039	VAV2
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	70.9×	0.039	VAV2
Constitutive Signaling by AKT1 E17K in Cancer	1	60.4×	0.039	TSC2
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	60.4×	0.039	GTF3C5
VEGFR2 mediated vascular permeability	1	58.3×	0.039	VAV2
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	58.3×	0.039	GTF3C5
DAP12 signaling	1	52.6×	0.039	VAV2
FCERI mediated Ca+2 mobilization	1	51.0×	0.039	VAV2
Interconversion of nucleotide di- and triphosphates	1	51.0×	0.039	AK8
FCERI mediated MAPK activation	1	49.4×	0.039	VAV2
RNA Polymerase III Transcription Initiation	1	48.0×	0.039	GTF3C5
RNA Polymerase III Transcription	1	46.6×	0.039	GTF3C5
GPVI-mediated activation cascade	1	44.1×	0.039	VAV2
Metabolism of nucleotides	1	42.9×	0.039	AK8
Developmental Lineage of Pancreatic Acinar Cells	1	42.9×	0.039	CEL
RNA Polymerase III Abortive And Retractive Initiation	1	39.8×	0.041	GTF3C5
Developmental Cell Lineages	1	32.0×	0.048	CEL
EPH-ephrin mediated repulsion of cells	1	31.4×	0.048	VAV2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of TOR signaling	2	112.3×	0.011	TSC1, TSC2
reorganization of cellular membranes to establish viral sites of replication	1	1685.2×	0.016	PI4KA
negative regulation of TORC1 signaling	2	64.8×	0.016	TSC1, TSC2
cellular response to starvation	2	38.7×	0.020	TSC1, TSC2
neural tube closure	2	37.5×	0.020	TSC1, TSC2
memory T cell differentiation	1	561.7×	0.021	TSC1
cellular response to decreased oxygen levels	1	421.3×	0.021	TSC1
regulation of small GTPase mediated signal transduction	2	28.8×	0.021	TSC2, VAV2
carbohydrate metabolic process	2	27.2×	0.021	GBGT1, ABO
pancreatic juice secretion	1	337.0×	0.024	CEL
5S class rRNA transcription by RNA polymerase III	1	280.9×	0.024	GTF3C5
transcription initiation at RNA polymerase III promoter	1	240.7×	0.024	GTF3C5
ceramide catabolic process	1	240.7×	0.024	CEL
immune response-regulating cell surface receptor signaling pathway	1	187.2×	0.024	VAV2
host-mediated perturbation of viral process	1	187.2×	0.024	PI4KA
negative regulation of ATP-dependent activity	1	168.5×	0.024	TSC1
negative regulation of cell size	1	168.5×	0.024	TSC1
regulation of insulin receptor signaling pathway	1	168.5×	0.024	TSC2
tRNA transcription by RNA polymerase III	1	153.2×	0.024	GTF3C5
negative regulation of mitophagy	1	153.2×	0.024	TSC2
regulation of hemopoiesis	1	153.2×	0.024	GFI1B
glycolipid biosynthetic process	1	140.4×	0.024	GBGT1
intestinal cholesterol absorption	1	140.4×	0.024	CEL
regulation of cell-matrix adhesion	1	129.6×	0.024	TSC1
anoikis	1	129.6×	0.024	TSC2
regulation of cell cycle	2	14.9×	0.024	TSC1, TSC2
negative regulation of macroautophagy	1	112.3×	0.027	TSC1
regulation of stress fiber assembly	1	99.1×	0.029	TSC1
ventricular system development	1	84.3×	0.031	AK8
obsolete D-glucose import	1	84.3×	0.031	TSC1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 9

Druggability breadth: 4 of 10 evidence-associated genes (40%) 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
PI4KA	ADENOSINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PI4KA	1	4
TSC1	0	0
TSC2	0	0
VAV2	0	0
CEL	0	0
GBGT1	0	0
AK8	0	0
GFI1B	0	0
GTF3C5	0	0
ABO	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADENOSINE	4	PI4KA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
PI4KA	86	Binding:83, Functional:2, ADMET:1
CEL	7	Binding:7
ABO	6	Binding:6
TSC2	1	Binding:1
GTF3C5	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CEL	3.1.1.13	sterol esterase
GBGT1	2.4.1.88	globoside alpha-N-acetylgalactosaminyltransferase
AK8	2.7.4.3	adenylate kinase
ABO	2.4.1.37, 2.4.1.40, 2.4.1.88	fucosylgalactoside 3-alpha-galactosyltransferase, glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase, globoside alpha-N-acetylgalactosaminyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
ADENOSINE	4	PI4KA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PI4KA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	CEL, ABO
D	Druggable family + AlphaFold only, no drug	2	GBGT1, AK8
E	Difficult family or no structure, no drug	5	TSC1, TSC2, VAV2, GFI1B, GTF3C5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TSC1	0	—
TSC2	1	—
VAV2	0	—
CEL	7	—
GBGT1	0	—
AK8	0	—
GFI1B	0	—
GTF3C5	1	—
ABO	6	—

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