TSC2

Summary

TSC2 (TSC complex subunit 2, HGNC:12363) is a protein-coding gene on chromosome 16p13.3, encoding Tuberin (P49815). 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 biosynthesis to promote cellular biomass…. In precision oncology, TSC2 Q1178* confers sensitivity to Everolimus in Thyroid Gland Carcinoma (CIViC Level C). It is a selective cancer dependency (DepMap: 18.5% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis.

Source: NCBI Gene 7249 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tuberous sclerosis 2 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 12,419 total — 1170 pathogenic, 237 likely-pathogenic
• Phenotypes (HPO): 121
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 10 cancer types
• Cancer dependency (DepMap): dependent in 18.5% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000548

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12363
Approved symbol	TSC2
Name	TSC complex subunit 2
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	tuberin, LAM, PPP1R160
Ensembl gene	ENSG00000103197
Ensembl biotype	protein_coding
OMIM	191092
Entrez	7249

Gene structure

Transcript identifiers

Ensembl transcripts: 88 — 37 protein_coding, 37 retained_intron, 10 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000219476, ENST00000350773, ENST00000382538, ENST00000401874, ENST00000439117, ENST00000439673, ENST00000461648, ENST00000463601, ENST00000463808, ENST00000467949, ENST00000471143, ENST00000483020, ENST00000488675, ENST00000490108, ENST00000497886, ENST00000561695, ENST00000562474, ENST00000563346, ENST00000568238, ENST00000568366, ENST00000568454, ENST00000568566, ENST00000568692, ENST00000569110, ENST00000569930, ENST00000642206, ENST00000642365, ENST00000642561, ENST00000642728, ENST00000642791, ENST00000642797, ENST00000642812, ENST00000642936, ENST00000643088, ENST00000643120, ENST00000643149, ENST00000643177, ENST00000643298, ENST00000643426, ENST00000643533, ENST00000643745, ENST00000643946, ENST00000644043, ENST00000644135, ENST00000644222, ENST00000644278, ENST00000644329, ENST00000644335, ENST00000644399, ENST00000644417, ENST00000644665, ENST00000644722, ENST00000644847, ENST00000645024, ENST00000645186, ENST00000645192, ENST00000645552, ENST00000645591, ENST00000646388, ENST00000646464, ENST00000646557, ENST00000646634, ENST00000646674, ENST00000646823, ENST00000647042, ENST00000647180, ENST00000647234, ENST00000647242, ENST00000715163, ENST00000715164, ENST00000903281, ENST00000903282, ENST00000903283, ENST00000903284, ENST00000903285, ENST00000903286, ENST00000903287, ENST00000903288, ENST00000903289, ENST00000903290, ENST00000903291, ENST00000920525, ENST00000920526, ENST00000941763, ENST00000941764, ENST00000941765, ENST00000941766, ENST00000941767

RefSeq mRNA: 43 — MANE Select: NM_000548 NM_000548, NM_001077183, NM_001114382, NM_001318827, NM_001318829, NM_001318831, NM_001318832, NM_001363528, NM_001370404, NM_001370405, NM_001406663, NM_001406664, NM_001406665, NM_001406667, NM_001406668, NM_001406670, NM_001406671, NM_001406673, NM_001406675, NM_001406676, NM_001406677, NM_001406678, NM_001406679, NM_001406680, NM_001406681, NM_001406682, NM_001406683, NM_001406684, NM_001406685, NM_001406686, NM_001406687, NM_001406688, NM_001406689, NM_001406690, NM_001406691, NM_001406692, NM_001406693, NM_001406694, NM_001406695, NM_001406696, NM_001406697, NM_001406698, NM_021055

CCDS: CCDS10458, CCDS10459, CCDS45384, CCDS58408, CCDS81932, CCDS81933, CCDS81934, CCDS92084, CCDS92085, CCDS92086

Canonical transcript exons

ENST00000219476 — 42 exons

Exon	Start	End
ENSE00000665078	2077598	2077726
ENSE00000873729	2053342	2053452
ENSE00000873731	2055402	2055519
ENSE00001908563	2047985	2048065
ENSE00003477944	2075799	2075892
ENSE00003479397	2070456	2070578
ENSE00003480783	2062972	2063053
ENSE00003505826	2072849	2072983
ENSE00003508344	2058747	2058873
ENSE00003514511	2072241	2072363
ENSE00003515047	2076491	2076585
ENSE00003515904	2086193	2086379
ENSE00003516607	2054296	2054440
ENSE00003518274	2086732	2086871
ENSE00003521540	2060670	2060813
ENSE00003530208	2061871	2062008
ENSE00003530548	2048587	2048753
ENSE00003531747	2081595	2081798
ENSE00003533430	2057105	2057178
ENSE00003549432	2080165	2080377
ENSE00003551596	2056644	2056769
ENSE00003559641	2064272	2064427
ENSE00003569705	2084228	2084715
ENSE00003576487	2071784	2071934
ENSE00003576976	2071510	2071616
ENSE00003590475	2084951	2085026
ENSE00003603845	2088048	2088139
ENSE00003615020	2050400	2050486
ENSE00003618010	2079032	2079196
ENSE00003621413	2079557	2079669
ENSE00003635863	2062497	2062600
ENSE00003638203	2076068	2076170
ENSE00003645603	2083695	2083816
ENSE00003653235	2065519	2065635
ENSE00003655946	2087863	2087941
ENSE00003656176	2088227	2088325
ENSE00003672725	2056196	2056244
ENSE00003683061	2079276	2079428
ENSE00003685929	2074200	2074389
ENSE00004013616	2085230	2085322
ENSE00004025935	2088446	2089491
ENSE00004025947	2082436	2082504

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 99.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.6218 / max 151.2561, expressed in 1805 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152187	10.0950	1790
152188	7.3270	1763
152186	0.1165	56
152190	0.0318	5
152189	0.0173	4
152193	0.0158	5
152191	0.0094	5
152192	0.0090	3

Top tissues by expression

302 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.50	gold quality
cerebellar hemisphere	UBERON:0002245	99.36	gold quality
cerebellar cortex	UBERON:0002129	99.27	gold quality
adenohypophysis	UBERON:0002196	99.11	gold quality
right uterine tube	UBERON:0001302	99.09	gold quality
right lobe of thyroid gland	UBERON:0001119	98.65	gold quality
sural nerve	UBERON:0015488	98.52	gold quality
left lobe of thyroid gland	UBERON:0001120	98.40	gold quality
right testis	UBERON:0004534	98.35	gold quality
left testis	UBERON:0004533	98.31	gold quality
right frontal lobe	UBERON:0002810	98.30	gold quality
pituitary gland	UBERON:0000007	98.28	gold quality
left ovary	UBERON:0002119	98.26	gold quality
right ovary	UBERON:0002118	98.21	gold quality
mucosa of stomach	UBERON:0001199	98.20	gold quality
metanephros cortex	UBERON:0010533	98.17	gold quality
body of uterus	UBERON:0009853	98.12	gold quality
endocervix	UBERON:0000458	98.11	gold quality
cerebellum	UBERON:0002037	98.11	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.05	gold quality
apex of heart	UBERON:0002098	97.90	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.88	gold quality
tibial nerve	UBERON:0001323	97.84	gold quality
lower esophagus	UBERON:0013473	97.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.71	gold quality
ganglionic eminence	UBERON:0004023	97.63	gold quality
body of stomach	UBERON:0001161	97.54	gold quality
left uterine tube	UBERON:0001303	97.53	gold quality
ectocervix	UBERON:0012249	97.42	gold quality
ascending aorta	UBERON:0001496	97.40	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	3.93
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ELF1, ESR1, HMGA2, MYC, NFATC3, NFKBIA, NFYA, TP53, TSC22D1, ZHX2

miRNA regulators (miRDB)

3 targeting TSC2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-5002-3P	95.75	67.04	542

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 18.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• missense mutation in the GTPase activating protein homology region in families with tuberous sclerosis complex (PMID:11403047)
• negative regulators of cell division; control of transition from G0/G1 to S phase (PMID:11686512)
• Detected two sequence changes involving the TSC2 stop codon. (PMID:11781698)
• calmodulin signaling in the propagation of this TSC2 activity (PMID:11811958)
• Fluorescence in situ hybridization analysis in a patient with an acrofacial dysostosis-like phenotype, tuberous sclerosis, and polycystic kidney disease shows a microdeletion of approximately 280 kb including the TSC2 gene on chromosome 16p13.3. (PMID:11836366)
• Novel TSC1 and TSC2 mutations in Japanese patients with tuberous sclerosis complex. (PMID:12015165)
• TSC1 and TSC2 mutations in tuberous sclerosis - used DHPLC analysis to facilitate the detection of a mosaic mutation, in the presence of a coexisting constitutional polymorphism. (PMID:12062115)
• effect on EHEN-induced renal and hepatocarcinogenesis in the suppressor gene transgenic rats (PMID:12127687)
• TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. (PMID:12172553)
• tuberin binds with 14-3-3 zeta to regulate phosphorylation of ribosomal protein S6 (PMID:12176984)
• hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1) (PMID:12271141)
• associates with 14-3-3 in vivo (PMID:12364343)
• TSC2 expression is regulated by 14-3-3 beta in human cells (PMID:12468542)
• A link exists between this protein and kidney diseases (PMID:12547695)
• Estrogen action induces tyrosine phosphatase activity that regulates stability of tuberin, which may play a crucial role in cellular specific functions such as endocytosis. (PMID:12581886)
• MK2 phosphorylates TSC2, which creates a 14-3-3 binding site and thus regulates the cellular function of the TSC2 tumor suppressor protein (PMID:12582162)
• Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. (PMID:12711473)
• We conclude that the hamartin/tuberin complex exerted a direct effect on the morphology and adhesive properties of 293 cells through regulation of the level and/or activity of cellular E-cadherin/beta-catenin (PMID:12766909)
• mutated in suberous sclerosis (REVIEW). (PMID:12773159)
• Mutated in tuberous sclerosis. (PMID:12773162)
• mutated in sporadic tumors (REVIEW) (PMID:12773163)
• TSC2 is a GAP for rheb and insulin-mediated rheb activation is PI3K dependent. (PMID:12820960)
• TSC2 binds to rheb and has a role in S6 kinase activation (PMID:12842888)
• Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. (PMID:12869586)
• Human TSC2 triggers mammalian cell size reduction and a dominant-negative TSC2 mutant induces increased size. (PMID:12894220)
• data support a model in which phosphorylation of hamartin regulates the function of the hamartin-tuberin complex during the G2/M phase of the cell cycle (PMID:14551205)
• the TSC1.TSC2 complex is regulated by pam and its ortholog highwire (PMID:14559897)
• Western blot analyses confirmed the deregulation of 14-3-3 proteins upon ectopic overexpression of TSC1 and TSC2. (PMID:14680818)
• TSC2 gene, which is responsible for tuberous sclerosis was identified, and all the exons of TSC2 were analyzed by using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) from peripheral blood of 28 patients . (PMID:14756965)
• A novel mechanism of post-translational inactivation of the TSC2 protein, tuberin, by physiologically inappropriate phosphorylation is demonstated. (PMID:14871804)
• people with TSC2 mutations were significantly more likely than those with TSC1 mutations to have autistic disorder, a low IQ, and a history of infantile spasms; low IQ was independently associated with both TSC2 mutations and a history of infantile spasm (PMID:14985384)
• Down regulation or loss of tuberin and/or hamartin expression may be permissive to fibrocyte proliferation or promote collagen production leading to fibroepithelial polyp formation. (PMID:15059224)
• Tuberin (TSC2) interact with smad2/smad3 during TGF-beta1 growth regulation. (PMID:15066998)
• tsc2 gene expression is reduced in the majority of subependymal giant cell astrocytomas (PMID:15072102)
• inhibition of B-Raf kinase via Rheb is an mTOR-independent function of tuberin (PMID:15150271)
• Binding with HPV16 E6 causes the proteasome-mediated degradation of Tuberin (PMID:15175323)
• Peutz-Jeghers syndrome and other benign tumor syndromes could be caused by dysregulation of the TSC2 pathway (PMID:15231735)
• To investigate the function of TSC2 and Rheb in mTOR signaling, we analyzed the TSC2-stimulated Rheb GTPase activity. (PMID:15340059)
• Tuberin has a role in binding p27 and negatively regulating its interaction with Skp2 (PMID:15355997)
• Cortical tuber giant cells in a case of epileptogenic tuberous sclerosis showed predominantly nuclear hamartin, cytosolic tuberin, and hyperphosphorylation of S6. (PMID:15477556)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tsc2	ENSDARG00000103125
danio_rerio		ENSDARG00000116122
mus_musculus	Tsc2	ENSMUSG00000002496
rattus_norvegicus	Tsc2	ENSRNOG00000011375
drosophila_melanogaster	gig	FBGN0005198

Paralogs (2): RALGAPA1 (ENSG00000174373), RALGAPA2 (ENSG00000188559)

Protein

Protein identifiers

Tuberin — P49815 (reviewed: P49815)

Alternative names: Tuberous sclerosis 2 protein

All UniProt accessions (24): P49815, A0A2R8Y5B2, A0A2R8Y5F1, A0A2R8Y670, A0A2R8Y692, A0A2R8Y6C9, A0A2R8Y7C8, A0A2R8Y7X5, A0A2R8YCR8, A0A2R8YDR3, A0A2R8YDZ2, A0A2R8YEJ8, A0A2R8YGD6, A0A2R8YGE6, A0A2R8YGU4, A0A2R8YHA2, H3BMQ0, H3BQK4, H3BQY7, I3L134, I3L3B1, Q5HYF7, X5D2U8, X5D7Q2

UniProt curated annotations — full annotation on UniProt →

Function. 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 biosynthesis to promote cellular biomass generation and growth. Within the TSC-TBC complex, TSC2 acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1. In absence of nutrients, the TSC-TBC complex inhibits mTORC1, thereby preventing phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) by the mTORC1 signaling. The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1. Involved in microtubule-mediated protein transport via its ability to regulate mTORC1 signaling. Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5.

Subunit / interactions. Component of the TSC-TBC complex (also named Rhebulator complex), composed of 2 molecules of TSC1, 2 molecules of TSC2 and 1 molecule of TBC1D7. Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2. Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23. Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex thereby stabilizing TSC2. Interacts with TSC1 and HERC1; the interaction with TSC1 stabilizes TSC2 and prevents the interaction with HERC1. May also interact with the adapter molecule RABEP1. The final complex may contain TSC2 and RABEP1 linked to RAB5. Interacts with HSPA1 and HSPA8. Interacts with NAA10 (via C-terminal domain). Interacts with RRAGA (polyubiquitinated). Interacts with WDR45B. Interacts with RPAP3 and URI1. Interacts with YWHAG. Interacts with RHEB. (Microbial infection) Interacts with human cytomegalovirus protein UL38; this interaction inhibits cellular stress response mediated by mTORC1.

Subcellular location. Lysosome membrane. Cytoplasm. Cytosol.

Tissue specificity. Liver, brain, heart, lymphocytes, fibroblasts, biliary epithelium, pancreas, skeletal muscle, kidney, lung and placenta.

Post-translational modifications. Phosphorylation at Ser-939 and Thr-1462 by PKB/AKT1 in response to insulin signaling and growth factor stimulation inhibits the ability of the TSC-TBC complex to suppress mTORC1 signaling: phosphorylation promotes dissociation of the TSC-TBC complex from lysosomal membranes, leading to activation of mTORC1 by RHEB. Phosphorylation at Ser-1387, Ser-1418 or Ser-1420 does not affect interaction with TSC1. Phosphorylation by AMPK activates it and leads to negative regulation of the mTORC1 complex. Phosphorylated at Ser-1798 by RPS6KA1; phosphorylation inhibits TSC2 ability to suppress mTORC1 signaling. Phosphorylated by DAPK1. Ubiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase complex, leading to its subsequent degradation. Ubiquitinated by MYCBP2 independently of its phosphorylation status leading to subsequent degradation; association with TSC1 protects from ubiquitination.

Disease relevance. Tuberous sclerosis 2 (TSC2) [MIM:613254] An autosomal dominant multi-system disorder that affects especially the brain, kidneys, heart, and skin. It is characterized by hamartomas (benign overgrowths predominantly of a cell or tissue type that occurs normally in the organ) and hamartias (developmental abnormalities of tissue combination). Clinical manifestations include epilepsy, learning difficulties, behavioral problems, and skin lesions. Seizures can be intractable and premature death can occur from a variety of disease-associated causes. The disease is caused by variants affecting the gene represented in this entry. Lymphangioleiomyomatosis (LAM) [MIM:606690] Progressive and often fatal lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. It affects almost exclusively young women and can occur as an isolated disorder or in association with tuberous sclerosis complex. The disease is caused by variants affecting the gene represented in this entry. Focal cortical dysplasia 2 (FCORD2) [MIM:607341] A form of focal cortical dysplasia, a malformation of cortical development that results in medically refractory epilepsy in the pediatric population and in adults. FCORD2 is a severe form, with onset usually in childhood, characterized by disrupted cortical lamination and specific cytological abnormalities. It is classified in 2 subtypes: type IIA characterized by dysmorphic neurons and lack of balloon cells; type IIB with dysmorphic neurons and balloon cells. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be due to an intron retention.

Isoforms (8)

UniProt ID	Names	Canonical?
P49815-1	1	yes
P49815-2	2
P49815-3	3
P49815-4	4
P49815-5	5
P49815-6	6
P49815-7	7
P49815-8	8, H, I

RefSeq proteins (43): NP_000539, NP_001070651, NP_001107854, NP_001305756, NP_001305758, NP_001305760, NP_001305761, NP_001350457, NP_001357333, NP_001357334, NP_001393592, NP_001393593, NP_001393594, NP_001393596, NP_001393597, NP_001393599, NP_001393600, NP_001393602, NP_001393604, NP_001393605, NP_001393606, NP_001393607, NP_001393608, NP_001393609, NP_001393610, NP_001393611, NP_001393612, NP_001393613, NP_001393614, NP_001393615, NP_001393616, NP_001393617, NP_001393618, NP_001393619, NP_001393620, NP_001393621, NP_001393622, NP_001393623, NP_001393624, NP_001393625, NP_001393626, NP_001393627, NP_066399 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000331	Rap/Ran_GAP_dom	Domain
IPR003913	Tuberin	Family
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR018515	Tuberin-type_domain	Domain
IPR024584	Tuberin_N	Domain
IPR027107	Tuberin/Ral-act_asu	Family
IPR035974	Rap/Ran-GAP_sf	Homologous_superfamily

Pfam: PF02145, PF03542, PF11864

UniProt features (272 total): sequence variant 94, helix 74, modified residue 22, strand 18, mutagenesis site 14, sequence conflict 13, turn 13, region of interest 8, compositionally biased region 7, splice variant 7, chain 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9CE3	ELECTRON MICROSCOPY	2.9
7DL2	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49815-F1	68.81	0.13

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (22): 540, 664, 927, 939, 981, 1130, 1132, 1155, 1271, 1337, 1338, 1346, 1364, 1387, 1411, 1418, 1420, 1452, 1462, 1764 …

Mutagenesis-validated functional residues (14):

Position	Phenotype
939	inhibits insulin-stimulated phosphorylation and activation of rps6kb1; when associated with a-1462.
1271	abolishes ampk-mediated phosphorylation; when associated with a-1387.
1387	abolishes ampk-mediated phosphorylation; when associated with a-1271.
1462	inhibits insulin-stimulated phosphorylation and activation of rps6kb1; when associated with a-939.
1529	decreased gtpase-activating protein activity.
1533	decreased gtpase-activating protein activity.
1594	decreased gtpase-activating protein activity.
1637–1639	abolishes gap activity.
1638	decreased gtpase-activating protein activity.
1639	decreased gtpase-activating protein activity.
1666	decreased gtpase-activating protein activity.
1745	abolishes gap activity.
1749–1751	no effect.
1749	decreased gtpase-activating protein activity.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-165181	Inhibition of TSC complex formation by AKT (PKB)
R-HSA-198323	AKT phosphorylates targets in the cytosol
R-HSA-380972	Energy dependent regulation of mTOR by LKB1-AMPK
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-8854214	TBC/RABGAPs

MSigDB gene sets: 519 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, REACTOME_MEMBRANE_TRAFFICKING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOMF_GTPASE_BINDING

GO Biological Process (29): neural tube closure (GO:0001843), protein import into nucleus (GO:0006606), endocytosis (GO:0006897), heart development (GO:0007507), intracellular protein localization (GO:0008104), negative regulation of cell population proliferation (GO:0008285), cellular response to starvation (GO:0009267), vesicle-mediated transport (GO:0016192), positive regulation of macroautophagy (GO:0016239), regulation of endocytosis (GO:0030100), negative regulation of Wnt signaling pathway (GO:0030178), negative regulation of TOR signaling (GO:0032007), anoikis (GO:0043276), regulation of insulin receptor signaling pathway (GO:0046626), negative regulation of insulin receptor signaling pathway (GO:0046627), positive chemotaxis (GO:0050918), regulation of small GTPase mediated signal transduction (GO:0051056), regulation of cell cycle (GO:0051726), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), negative regulation of mitophagy (GO:1901525), negative regulation of TORC1 signaling (GO:1904262), cytoplasmic translation (GO:0002181), regulation of macroautophagy (GO:0016241), cellular response to nutrient levels (GO:0031669), TORC1 signaling (GO:0038202), positive regulation of GTPase activity (GO:0043547), negative regulation of translational initiation (GO:0045947), positive regulation of translational initiation (GO:0045948), positive regulation of TORC1 signaling (GO:1904263)

GO Molecular Function (6): GTPase activator activity (GO:0005096), phosphatase binding (GO:0019902), small GTPase binding (GO:0031267), protein homodimerization activity (GO:0042803), Hsp90 protein binding (GO:0051879), protein binding (GO:0005515)

GO Cellular Component (11): nucleus (GO:0005634), cytoplasm (GO:0005737), lysosome (GO:0005764), lysosomal membrane (GO:0005765), Golgi apparatus (GO:0005794), cytosol (GO:0005829), postsynaptic density (GO:0014069), membrane (GO:0016020), TSC1-TSC2 complex (GO:0033596), perinuclear region of cytoplasm (GO:0048471), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
MTOR signalling	2
Autophagy	1
PIP3 activates AKT signaling	1
Transcriptional Regulation by TP53	1
PI3K/AKT Signaling in Cancer	1
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
negative regulation of signal transduction	2
negative regulation of intracellular signal transduction	2
insulin receptor signaling pathway	2
intracellular membrane-bounded organelle	2
primary neural tube formation	1
tube closure	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
animal organ development	1
circulatory system development	1
macromolecule localization	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
transport	1
cellular process	1
positive regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
endocytosis	1
regulation of cellular component organization	1
regulation of vesicle-mediated transport	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
TOR signaling	1
regulation of TOR signaling	1
apoptotic process	1
regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1

Protein interactions and networks

STRING

3586 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSC2	TSC1	Q92574	999
TSC2	TBC1D7	Q9P0N9	998
TSC2	RHEB	Q15382	997
TSC2	USP6	P35125	984
TSC2	MTOR	P42345	962
TSC2	RPS6KB1	P23443	943
TSC2	PKD1	P98161	941
TSC2	RASA1	P20936	928
TSC2	RPTOR	Q8N122	918
TSC2	DDIT4	Q9NX09	916
TSC2	RPS6	P08227	906
TSC2	RICTOR	Q6R327	901
TSC2	PTEN	P60484	890
TSC2	SESN1	Q9Y6P5	886
TSC2	RPS6KB2	Q9UBS0	878

IntAct

199 interactions, top by confidence:

A	B	Type	Score
TSC2	YWHAB	psi-mi:“MI:0915”(physical association)	0.950
TSC2	YWHAB	psi-mi:“MI:0914”(association)	0.950
YWHAB	TSC2	psi-mi:“MI:0407”(direct interaction)	0.950
YWHAB	TSC2	psi-mi:“MI:0915”(physical association)	0.950
YWHAB	TSC2	psi-mi:“MI:0914”(association)	0.950
YWHAZ	TSC2	psi-mi:“MI:0915”(physical association)	0.940
TSC2	YWHAZ	psi-mi:“MI:0915”(physical association)	0.940
YWHAZ	TSC2	psi-mi:“MI:0407”(direct interaction)	0.940
YWHAZ	TSC2	psi-mi:“MI:0914”(association)	0.940
TSC2	YWHAZ	psi-mi:“MI:0914”(association)	0.940
TSC2	TSC1	psi-mi:“MI:0915”(physical association)	0.930
TSC1	TSC2	psi-mi:“MI:0915”(physical association)	0.930
TSC1	TSC2	psi-mi:“MI:0403”(colocalization)	0.930
TSC1	TSC2	psi-mi:“MI:0914”(association)	0.930

BioGRID (350): TSC2 (Affinity Capture-Western), TSC2 (Affinity Capture-Western), TSC1 (Affinity Capture-Western), TSC2 (Affinity Capture-Western), SIRT1 (Affinity Capture-Western), TSC2 (Affinity Capture-Western), TSC2 (Affinity Capture-Western), RRAGA (Affinity Capture-Western), RRAGB (Affinity Capture-Western), RRAGC (Affinity Capture-Western), RRAGD (Affinity Capture-Western), TSC2 (Affinity Capture-Western), TSC2 (Affinity Capture-Western), TSC2 (Affinity Capture-MS), TSC2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4K859, A1Z7L1, A1ZBE8, A8WTE8, F4JC97, F4KBW6, F6S215, F6WXT2, O13665, O60287, O75691, P34343, P40090, P42173, P48322, P49815, P49816, P78527, P78847, Q03280, Q09716, Q21106, Q571H0, Q5SRE5, Q5WNI9, Q61037, Q6ZQH8, Q750S2, Q8BH53, Q8IQV9, Q8MYL1, Q8QGX4, Q8WN22, Q93903, Q95YE9, Q9C8Z4, Q9DEI1, Q9FIN7, Q9HDV6, Q9P7M6

Diamond homologs: A2ALS5, A5PF44, G3X9J0, O35412, O43166, O60292, P46062, P47736, P49815, P49816, Q3V0G7, Q54EH3, Q55AN8, Q5JCS6, Q5SVL6, Q5VVW2, Q5ZJY3, Q5ZMV8, Q61037, Q684P5, Q75J96, Q80TE4, Q8C0T5, Q96FS4, Q9P2F8, A3KGS3, O55007, P86409, P86411, Q2PPJ7, Q54SS8, Q6GYP7, Q6GYQ0, Q9UUG9, Q9VB98, Q54TK4

SIGNOR signaling

46 interactions.

A	Effect	B	Mechanism
TSC2	“down-regulates activity”	RHEB	“gtpase-activating protein”
RPS6KA1	down-regulates	TSC2	phosphorylation
MAPK1	down-regulates	TSC2	phosphorylation
GSK3A	up-regulates	TSC2	phosphorylation
PRKAA2	up-regulates	TSC2	phosphorylation
CHUK	down-regulates	TSC2	phosphorylation
AKT2	down-regulates	TSC2	phosphorylation
MAPK3	“down-regulates activity”	TSC2	phosphorylation
AMPK	up-regulates	TSC2	phosphorylation
TSC2	“form complex”	TSC	binding
ERK1/2	“down-regulates activity”	TSC2	phosphorylation
ERK1/2	down-regulates	TSC2	phosphorylation
RPS6K	down-regulates	TSC2	phosphorylation
UBE3A	“down-regulates quantity by destabilization”	TSC2	ubiquitination
CyclinD/CDK4	“up-regulates activity”	TSC2	phosphorylation
CyclinD1/CDK6	“up-regulates activity”	TSC2	phosphorylation
PRKCD	“down-regulates activity”	TSC2	phosphorylation
DDIT4	“up-regulates activity”	TSC2	binding
MYCBP2	“down-regulates quantity by destabilization”	TSC2	ubiquitination
PRKAA1	“up-regulates activity”	TSC2	phosphorylation
SGK3	“up-regulates activity”	TSC2	phosphorylation
TSC2	“up-regulates activity”	TSC1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	8	60.3×	6e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	53.2×	2e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	46.6×	7e-09
Activation of BH3-only proteins	8	39.3×	2e-09
FOXO-mediated transcription	8	26.6×	4e-08
Intrinsic Pathway for Apoptosis	9	26.1×	5e-09
RHO GTPases activate PKNs	7	22.0×	1e-06
SARS-CoV-1-host interactions	9	15.7×	4e-07

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	14.1×	9e-03
intracellular protein localization	11	8.9×	6e-05
protein phosphorylation	11	5.8×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 10 cancer types — ANGS, BLCA, CHOL, CHRCC, ESCA, HCC, PANCREAS, PANET, SCLC, STAD.

Clinical variants and AI predictions

ClinVar

12419 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1170
Likely pathogenic	237
Uncertain significance	4381
Likely benign	2542
Benign	283

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012388	NM_000548.5(TSC2):c.1610_1617dup (p.Ser540fs)	Pathogenic
1013087	NM_000548.5(TSC2):c.3190_3285-15del	Pathogenic
1028339	NM_000548.5(TSC2):c.1258-2A>G	Pathogenic
1028343	NM_000548.5(TSC2):c.600-2A>T	Pathogenic
1042872	NM_000548.5(TSC2):c.3179G>C (p.Trp1060Ser)	Pathogenic
1045993	NM_000548.5(TSC2):c.4930G>T (p.Asp1644Tyr)	Pathogenic
1068040	NM_000548.5(TSC2):c.4834_4850-95del	Pathogenic
1068227	NM_000548.5(TSC2):c.551T>A (p.Val184Asp)	Pathogenic
1068835	NM_000548.5(TSC2):c.3397+1G>T	Pathogenic
1069474	NC_000016.9:g.(?2103337)(2110820_?)del	Pathogenic
1069644	NM_000548.5(TSC2):c.4827C>A (p.Cys1609Ter)	Pathogenic
1069923	NM_000548.5(TSC2):c.5377_5378insT (p.Arg1793fs)	Pathogenic
1069935	NM_000548.5(TSC2):c.138+5G>C	Pathogenic
1070034	NM_000548.5(TSC2):c.4013_4014del (p.Ser1338fs)	Pathogenic
1070242	NM_000548.5(TSC2):c.5103_5104del (p.Lys1701fs)	Pathogenic
1070243	NM_000548.5(TSC2):c.3434del (p.Pro1145fs)	Pathogenic
1071233	NM_000548.5(TSC2):c.2687_2690dup (p.Phe897fs)	Pathogenic
1071355	NM_000548.5(TSC2):c.3505del (p.Ala1169fs)	Pathogenic
1071378	NC_000016.9:g.(?_2025180)_2130380del	Pathogenic
1071380	NC_000016.9:g.(?2120437)(2123004_?)del	Pathogenic
1071381	NC_000016.9:g.(?2098597)(2108894_?)del	Pathogenic
1072019	NM_000548.5(TSC2):c.810_811dup (p.Ser271fs)	Pathogenic
1072368	NM_000548.5(TSC2):c.2166dup (p.Ile723fs)	Pathogenic
1072481	NM_000548.5(TSC2):c.4756del (p.Asp1586fs)	Pathogenic
1072663	NM_000548.5(TSC2):c.3582G>A (p.Trp1194Ter)	Pathogenic
1072814	NM_000548.5(TSC2):c.2285T>A (p.Leu762Ter)	Pathogenic
1072867	NM_000548.5(TSC2):c.3316A>T (p.Lys1106Ter)	Pathogenic
1073182	NC_000016.9:g.(?2115510)(2115646_?)del	Pathogenic
1073382	NM_000548.5(TSC2):c.4440_4441insT (p.Lys1481Ter)	Pathogenic
1073460	NC_000016.10:g.2072241_2072247dup	Pathogenic

SpliceAI

8135 predictions. Top by Δscore:

Variant	Effect	Δscore
16:2047971:G:GT	donor_gain	1.0000
16:2050388:A:AG	acceptor_gain	1.0000
16:2050389:T:G	acceptor_gain	1.0000
16:2050395:TCCAG:T	acceptor_loss	1.0000
16:2050396:CCAGG:C	acceptor_loss	1.0000
16:2050397:CAGG:C	acceptor_loss	1.0000
16:2050398:A:AG	acceptor_gain	1.0000
16:2050398:AG:A	acceptor_gain	1.0000
16:2050398:AGGAA:A	acceptor_loss	1.0000
16:2050399:G:GG	acceptor_gain	1.0000
16:2050399:GG:G	acceptor_gain	1.0000
16:2050484:GAG:G	donor_gain	1.0000
16:2050487:G:GC	donor_loss	1.0000
16:2050487:G:GG	donor_gain	1.0000
16:2050488:T:A	donor_loss	1.0000
16:2053330:T:TA	acceptor_gain	1.0000
16:2053333:T:A	acceptor_gain	1.0000
16:2053334:G:A	acceptor_gain	1.0000
16:2053336:T:TA	acceptor_gain	1.0000
16:2053339:CAG:C	acceptor_loss	1.0000
16:2053340:A:AG	acceptor_gain	1.0000
16:2053340:AGC:A	acceptor_loss	1.0000
16:2053340:AGCAC:A	acceptor_gain	1.0000
16:2053341:G:GT	acceptor_gain	1.0000
16:2053341:GC:G	acceptor_gain	1.0000
16:2053341:GCAC:G	acceptor_gain	1.0000
16:2053341:GCACG:G	acceptor_gain	1.0000
16:2054408:G:GT	donor_gain	1.0000
16:2054428:G:GT	donor_gain	1.0000
16:2054431:G:GT	donor_gain	1.0000

AlphaMissense

11728 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:2058808:T:A	W304R	1.000
16:2058808:T:C	W304R	1.000
16:2074375:T:C	L844P	1.000
16:2075862:C:A	A870D	1.000
16:2075871:T:C	L873P	1.000
16:2076069:T:C	F881L	1.000
16:2076071:T:A	F881L	1.000
16:2076071:T:G	F881L	1.000
16:2076091:T:C	L888P	1.000
16:2076094:C:A	A889D	1.000
16:2076114:T:A	W896R	1.000
16:2076114:T:C	W896R	1.000
16:2076117:T:C	F897L	1.000
16:2076118:T:C	F897S	1.000
16:2076119:C:A	F897L	1.000
16:2076119:C:G	F897L	1.000
16:2076495:T:C	L916P	1.000
16:2079322:T:A	W1060R	1.000
16:2079322:T:C	W1060R	1.000
16:2079326:T:C	L1061P	1.000
16:2079341:T:C	L1066P	1.000
16:2079344:T:A	V1067D	1.000
16:2080347:T:A	W1194R	1.000
16:2080347:T:C	W1194R	1.000
16:2080350:G:C	A1195P	1.000
16:2080366:G:C	R1200P	1.000
16:2080377:G:T	G1204W	1.000
16:2081595:G:A	G1204E	1.000
16:2081606:T:A	W1208R	1.000
16:2081606:T:C	W1208R	1.000

dbSNP variants (sampled 300 via entrez): RS1000026519 (16:2080687 T>A,C), RS1000122133 (16:2049036 T>C), RS1000130165 (16:2076973 C>T), RS1000139988 (16:2046913 A>G), RS1000189044 (16:2066607 C>A,G,T), RS1000202234 (16:2066997 C>T), RS1000333394 (16:2053609 T>C,G), RS1000362725 (16:2077279 C>G,T), RS1000383530 (16:2087292 C>A,G,T), RS1000386933 (16:2086138 G>A,C,T), RS1000442583 (16:2057456 A>C), RS1000576492 (16:2046148 C>A,G,T), RS1000593901 (16:2074017 C>G,T), RS1000616615 (16:2066470 A>G), RS1000647107 (16:2070167 C>T)

Disease associations

OMIM: gene MIM:191092 | disease phenotypes: MIM:613254, MIM:191100, MIM:606690, MIM:607341, MIM:167000, MIM:601494, MIM:613690, MIM:219700, MIM:603592, MIM:142623, MIM:259500, MIM:619681, MIM:615963, MIM:601626, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
tuberous sclerosis 2	Definitive	Autosomal dominant
lymphangioleiomyomatosis	Strong	Autosomal dominant
tuberous sclerosis complex	Supportive	Autosomal dominant

Mondo (33): tuberous sclerosis 2 (MONDO:0013199), hereditary neoplastic syndrome (MONDO:0015356), tuberous sclerosis (MONDO:0001734), lymphangioleiomyomatosis (MONDO:0011705), isolated focal cortical dysplasia type II (MONDO:0011818), autism spectrum disorder (MONDO:0005258), cystic kidney disease (MONDO:0002473), congenital nervous system disorder (MONDO:0002320), neurodevelopmental disorder (MONDO:0700092), ovarian cancer (MONDO:0008170), dilated cardiomyopathy 1D (MONDO:0011095), hypertrophic cardiomyopathy 7 (MONDO:0013369), tuberous sclerosis 1 (MONDO:0008612), intellectual disability (MONDO:0001071), cystic fibrosis (MONDO:0009061)

Orphanet (19): Inherited cancer-predisposing syndrome (Orphanet:140162), Tuberous sclerosis complex (Orphanet:805), Isolated focal cortical dysplasia type II (Orphanet:268994), Lymphangioleiomyomatosis (Orphanet:538), Rare ovarian cancer (Orphanet:213500), Familial isolated dilated cardiomyopathy (Orphanet:154), Left ventricular noncompaction (Orphanet:54260), Cystic fibrosis (Orphanet:586), Autosomal dominant polycystic kidney disease (Orphanet:730), Hereditary xanthinuria (Orphanet:3467), Xanthinuria type II (Orphanet:93602), Hirschsprung disease (Orphanet:388), Neuroblastoma (Orphanet:635), Osteosarcoma (Orphanet:668), Familial vesicoureteral reflux (Orphanet:289365)

HPO phenotypes

121 total (30 of 121 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000077	Abnormality of the kidney
HP:0000083	Renal insufficiency
HP:0000107	Renal cyst
HP:0000113	Polycystic kidney dysplasia
HP:0000169	Gingival fibromatosis
HP:0000238	Hydrocephalus
HP:0000365	Hearing impairment
HP:0000648	Optic atrophy
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000739	Anxiety
HP:0000752	Hyperactivity
HP:0000790	Hematuria
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0000826	Precocious puberty
HP:0000957	Cafe-au-lait spot
HP:0001000	Abnormality of skin pigmentation
HP:0001004	Lymphedema
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001269	Hemiparesis
HP:0001328	Specific learning disability
HP:0001407	Hepatic cysts
HP:0001442	Typified by somatic mosaicism

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001762_12	Obesity-related traits	5.000000e-06
GCST005231_22	Major depressive disorder	9.000000e-06
GCST90002407_551	White blood cell count	7.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004626	IGFBP-3 measurement

MeSH disease descriptors (22)

Descriptor	Name	Tree numbers
D003550	Cystic Fibrosis	C06.689.202; C08.381.187; C16.320.190; C16.614.213
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D004827	Epilepsy	C10.228.140.490
D006222	Hamartoma	C04.445
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D052177	Kidney Diseases, Cystic	C12.050.351.968.419.403; C12.200.777.419.403; C12.950.419.403
D015470	Leukemia, Myeloid, Acute	C04.557.337.539.275; C15.378.508.539.275
D018192	Lymphangioleiomyomatosis	C04.557.375.460.465; C04.557.450.692.500; C15.604.515.562.465; C20.683.515.710.465
D009369	Neoplasms	C04
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D009447	Neuroblastoma	C04.557.465.625.600.590.650.550; C04.557.470.670.590.650.550; C04.557.580.625.600.590.650.550
D065886	Neurodevelopmental Disorders	F03.625
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D016891	Polycystic Kidney, Autosomal Dominant	C12.050.351.968.419.403.875.500; C12.200.777.419.403.875.500; C12.950.419.403.875.500; C16.131.077.717.500; C16.320.184.625.500
D012207	Rhabdomyoma	C04.557.450.590.540.700
D014402	Tuberous Sclerosis	C04.445.810; C04.651.800; C04.700.700; C10.500.507.400.750; C10.562.850; C10.574.500.865; C16.131.666.507.400.750; C16.320.400.880; C16.320.700.700
C566906	Cakut (supp.)
C563306	Cardiomyopathy, Dilated, 1D (supp.)
C537067	Focal cortical dysplasia of Taylor (supp.)
C565346	Tuberous Sclerosis 1 (supp.)
C566021	Tuberous Sclerosis 2 (supp.)
C566358	Xanthinuria, Type II (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067627 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
TSC2 Q1178*	Everolimus	Thyroid Gland Carcinoma	Sensitivity/Response	CIViC C	EID1108

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

77 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression, affects localization, affects reaction	4
Resveratrol	increases expression, increases reaction, decreases reaction, increases phosphorylation, increases activity (+3 more)	3
Acetaminophen	decreases expression, increases expression	3
bisphenol A	decreases expression, increases methylation	2
Air Pollutants	affects expression, affects cotreatment, increases abundance, increases expression, increases oxidation	2
Azacitidine	affects expression, affects methylation, decreases methylation, increases expression	2
Cisplatin	decreases expression, increases activity, increases phosphorylation	2
Ozone	affects cotreatment, increases expression, increases oxidation, increases abundance, affects expression	2
Quercetin	increases expression, increases phosphorylation	2
Cadmium Chloride	decreases expression, increases expression	2
Sirolimus	increases reaction, decreases expression, decreases reaction, affects cotreatment, decreases phosphorylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
moringin	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases expression, increases oxidation, increases abundance, affects cotreatment	1
4-hydroxy-2-nonenal	decreases expression	1
methacrylaldehyde	increases expression, increases oxidation, increases abundance, affects cotreatment	1
mercuric bromide	decreases expression, affects cotreatment	1
M-VAC protocol	decreases response to substance	1
4-phenylbutyric acid	increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases reaction, affects binding, decreases reaction	1
6-formylindolo(3,2-b)carbazole	decreases expression, decreases reaction	1
temsirolimus	affects cotreatment, decreases phosphorylation	1
alpinetin	affects reaction, increases expression, increases cleavage, increases phosphorylation, increases lipidation (+4 more)	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5662281	Binding	Inhibition of TSC-2 phosphorylation at ser-1462 residue in human A549 cells measured after 3 hrs by immunoblotting analysis	Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. — J Natl Cancer Inst

Cellosaurus cell lines

84 cell lines: 36 cancer cell line, 36 transformed cell line, 7 induced pluripotent stem cell, 4 finite cell line, 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0485	PLC/PRF/5	Cancer cell line	Male
CVCL_1216	EW-3	Cancer cell line	Male
CVCL_1N87	GM06101	Transformed cell line	Female
CVCL_1N88	GM06102	Finite cell line	Female
CVCL_1N89	GM25318	Induced pluripotent stem cell	Female
CVCL_3985	BON-1	Cancer cell line	Male
CVCL_5102	SNU-878	Cancer cell line	Female
CVCL_5L48	GM03933	Transformed cell line	Female
CVCL_5L49	GM03958	Finite cell line	Female
CVCL_5L50	GM04519	Transformed cell line	Female

Clinical trials (associated diseases)

157 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00989742	PHASE4	COMPLETED	Doxycycline In Lymphangioleiomyomatosis (LAM)
NCT05044819	PHASE4	ACTIVE_NOT_RECRUITING	Assessment of Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution
NCT00414648	PHASE3	COMPLETED	Efficacy and Safety of Sirolimus in LAM
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)
NCT03150914	PHASE3	ACTIVE_NOT_RECRUITING	Multicenter Interventional Lymphangioleiomyomatosis (LAM) Early Disease Trial
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)
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)
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
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
NCT05534672	PHASE3	RECRUITING	Placebo Controlled Study to Assess the Efficacy and Safety of Rapamycin in Drug Resistant Epilepsy Associated With Tuberous Sclerosis Complex
NCT05604170	PHASE3	TERMINATED	Open-label Study of Adjunctive GNX Treatment in Children and Adults With TSC-related Epilepsy
NCT07403266	PHASE3	RECRUITING	Treatment With Full-spectrum Cannabis Extract of Refractory Epilepsy Associated With Tuberous Sclerosis Complex (TSC)
NCT02201212	PHASE2	COMPLETED	Everolimus for Cancer With TSC1 or TSC2 Mutation
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)
NCT00005906	PHASE2	COMPLETED	Treatment With Octreotide in Patients With Lymphangioleiomyomatosis
NCT00457808	PHASE2	COMPLETED	Rapamycin Therapy for Patients With Tuberous Sclerosis Complex and Sporadic LAM
NCT00490789	PHASE2	UNKNOWN	Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM
NCT01059318	PHASE2	COMPLETED	A Study to Determine the Safety and Effectiveness of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis
NCT01353209	PHASE2	COMPLETED	Letrozole for Lymphangioleiomyomatosis
NCT02484664	PHASE2	COMPLETED	COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC
NCT02737202	PHASE2	TERMINATED	Safety and Efficacy of Saracatinib In Subjects With Lymphangioleiomyomatosis
NCT03062943	PHASE2	COMPLETED	A Study of Nintedanib for LymphAngioleioMyomatosis (LAM)
NCT03253913	PHASE2	COMPLETED	Resveratrol and Sirolimus in Lymphangioleiomyomatosis Trial
NCT03304678	PHASE2	COMPLETED	Discovery of Sirolimus Sensitive Biomarkers in Blood
NCT05190627	PHASE2	UNKNOWN	Effect of Loratadine in Lymphangioleiomyomatosis
NCT00126672	PHASE2	COMPLETED	RAPAMYCIN FOR KIDNEY ANGIOMYOLIPOMAS
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
NCT02104011	PHASE2	COMPLETED	Treatment of Renal Angiomyolipomas in Tuberous Sclerosis by Beta-blockers
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
NCT03363763	PHASE2	TERMINATED	Topical Sirolimus Ointment for Cutaneous Angiofibromas in Subjects With Tuberous Sclerosis Complex
NCT04285346	PHASE2	COMPLETED	Adjunctive Ganaxolone Treatment (Part A) in TSC Followed by Long-term Treatment (Part B)