TBC1D1

Summary

TBC1D1 (TBC1 domain family member 1, HGNC:11578) is a protein-coding gene on chromosome 4p14, encoding TBC1 domain family member 1 (Q86TI0). May act as a GTPase-activating protein for Rab family protein(s).

TBC1D1 is the founding member of a family of proteins sharing a 180- to 200-amino acid TBC domain presumed to have a role in regulating cell growth and differentiation. These proteins share significant homology with TRE2 (USP6; MIM 604334), yeast Bub2, and CDC16 (MIM 603461) (White et al., 2000 [PubMed 10965142]).

Source: NCBI Gene 23216 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic renal or urinary tract malformation (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 26
• Clinical variants (ClinVar): 251 total
• MANE Select transcript: NM_001396959

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11578
Approved symbol	TBC1D1
Name	TBC1 domain family member 1
Location	4p14
Locus type	gene with protein product
Status	Approved
Aliases	TBC, TBC1, KIAA1108
Ensembl gene	ENSG00000065882
Ensembl biotype	protein_coding
OMIM	609850
Entrez	23216

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 26 protein_coding, 7 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000261439, ENST00000401554, ENST00000402522, ENST00000405444, ENST00000406664, ENST00000407365, ENST00000421339, ENST00000443855, ENST00000446803, ENST00000469803, ENST00000475531, ENST00000491553, ENST00000492180, ENST00000508802, ENST00000509761, ENST00000510573, ENST00000511238, ENST00000513936, ENST00000698857, ENST00000698858, ENST00000859644, ENST00000859645, ENST00000859646, ENST00000859647, ENST00000859648, ENST00000859649, ENST00000859650, ENST00000859651, ENST00000936240, ENST00000936241, ENST00000961337, ENST00000961338, ENST00000961339, ENST00000961340, ENST00000961341, ENST00000961342, ENST00000961343

RefSeq mRNA: 6 — MANE Select: NM_001396959 NM_001253912, NM_001253913, NM_001253914, NM_001253915, NM_001396959, NM_015173

CCDS: CCDS33972, CCDS58897, CCDS93491

Canonical transcript exons

ENST00000698857 — 22 exons

Exon	Start	End
ENSE00000969645	38014509	38014973
ENSE00000969647	38020591	38020695
ENSE00001157515	38137135	38139173
ENSE00001340229	37902003	37902512
ENSE00003466897	38115710	38115954
ENSE00003494705	38045817	38045903
ENSE00003568045	38133084	38133257
ENSE00003573065	38018354	38018443
ENSE00003574837	38124962	38125131
ENSE00003588959	38044362	38044490
ENSE00003631840	38035588	38035698
ENSE00003648483	38118033	38118192
ENSE00003688990	38054199	38054338
ENSE00003716953	38027788	38027879
ENSE00003725872	38102999	38103157
ENSE00003730893	38021586	38021718
ENSE00003745389	38049618	38049898
ENSE00003752979	38095929	38096090
ENSE00003787342	38089932	38090117
ENSE00003848709	37891084	37891348
ENSE00003974999	38051899	38052060
ENSE00003975003	38053106	38053225

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.8196 / max 446.2443, expressed in 1787 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47309	9.4288	1148
47314	8.0650	1663
47312	6.3019	1644
47313	2.8567	1256
47315	0.3445	166
47308	0.3104	116
47307	0.3011	141
47305	0.1612	64
47306	0.0499	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.10	gold quality
body of uterus	UBERON:0009853	98.95	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.46	gold quality
right coronary artery	UBERON:0001625	98.21	gold quality
metanephros cortex	UBERON:0010533	98.10	gold quality
ganglionic eminence	UBERON:0004023	98.06	gold quality
popliteal artery	UBERON:0002250	97.95	gold quality
tibial artery	UBERON:0007610	97.95	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.95	gold quality
lower esophagus	UBERON:0013473	97.91	gold quality
mucosa of stomach	UBERON:0001199	97.75	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.73	gold quality
aorta	UBERON:0000947	97.65	gold quality
left coronary artery	UBERON:0001626	97.64	gold quality
coronary artery	UBERON:0001621	97.36	gold quality
ascending aorta	UBERON:0001496	97.35	gold quality
thoracic aorta	UBERON:0001515	97.33	gold quality
myometrium	UBERON:0001296	97.25	gold quality
descending thoracic aorta	UBERON:0002345	97.09	gold quality
right lobe of thyroid gland	UBERON:0001119	96.99	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.99	gold quality
left lobe of thyroid gland	UBERON:0001120	96.92	gold quality
right atrium auricular region	UBERON:0006631	96.81	gold quality
left uterine tube	UBERON:0001303	96.75	gold quality
gastrocnemius	UBERON:0001388	96.65	gold quality
thyroid gland	UBERON:0002046	96.57	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.55	gold quality
heart left ventricle	UBERON:0002084	96.34	gold quality
gall bladder	UBERON:0002110	96.30	gold quality
muscle of leg	UBERON:0001383	96.23	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	35.04
E-CURD-114	yes	11.15
E-GEOD-99795	no	145.98
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MITF

miRNA regulators (miRDB)

80 targeting TBC1D1, 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-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-1200	99.71	70.42	1838

Literature-anchored findings (GeneRIF, showing 20)

• coding variant R125W affects obesity susceptibility, delimits the location of an obesity gene at 4q34-35 and identifies a gene/gene interaction that influences the risk for obesity predisposition (PMID:16893906)
• form of Tbc1d1 also inhibited GLUT4 translocation and that this effect also required a functional GAP domain (PMID:17274760)
• These results confirm a putative role of TBC1D1 R125W variant in familial obesity predisposition. (PMID:18325908)
• TBC1D1 is Ser237 phosphorylated and binding capacity to 14-3-3 protein is increased in skeletal muscle following exercise. (PMID:20837646)
• [review] The question of a mechanism for increased phosphorylation of Ser237-TBC1D1 after exercise has, so far, not had a straightforward experimental approach for a direct answer in humans undergoing in vivo exercise. (PMID:21078596)
• Crystal structures of human TBC1D1 and TBC1D4 (AS160) RabGTPase-activating protein (RabGAP) domains reveal critical elements for GLUT4 translocation. (PMID:21454505)
• A single bout of exercise regulates TBC1D1 and AS160 phosphorylation on multiple sites in human skeletal muscle. (PMID:21505148)
• Data suggest that insulin increases phosphorylation of signaling nexus TBC1D1 independent of prior exercise or lipid/Intralipid administration. (PMID:22851577)
• Moderate association of rs9852 indicates an influence of TBC1D1 for antipsychotic-induced weight gain. (PMID:23364847)
• R125W mutation occurs in a location of the TBC1D1 PTB domain that is predicted to have a function in a putative protein:protein interaction. (PMID:23667688)
• Data show that TBC1D1 is expressed and phosphorylated in response to glucose in these cells. (PMID:24239544)
• AS160 and TBC1D1 phosphorylations were evident 30 min after exercise. (PMID:24876356)
• data demonstrate heterozygous deactivating TBC1D1 mutations in CAKUT patients with a similar renal and ureteral phenotype, and provide evidence that TBC1D1 mutations may contribute to CAKUT (PMID:26572137)
• TBC1D1-Ser(231) phosphorylation and/or 14-3-3 binding partially mediates AMPK-governed glucose homeostasis and muscle glucose uptake in a context-dependent manner. (PMID:27826658)
• Sex and fiber type independently influence AMPK, TBC1D1, and TBC1D4 at rest and during recovery from high-intensity exercise in humans. (PMID:31895596)
• TBC1D1 interacting proteins, VPS13A and VPS13C, regulate GLUT4 homeostasis in C2C12 myotubes. (PMID:33087848)
• Does TBC1D4 (AS160) or TBC1D1 Deficiency Affect the Expression of Fatty Acid Handling Proteins in the Adipocytes Differentiated from Human Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Obtained from Subcutaneous and Visceral Fat Depots? (PMID:34208471)
• TBC1D1 represses glioma progression by altering the integrity of the cytoskeleton. (PMID:38189823)
• Novel prognostic biomarker TBC1D1 is associated with immunotherapy resistance in gliomas. (PMID:38529286)
• TBC1D1 is an energy-responsive polarization regulator of macrophages via governing ROS production in obesity. (PMID:38902450)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbc1d1	ENSDARG00000062081
mus_musculus	Tbc1d1	ENSMUSG00000029174
rattus_norvegicus	Tbc1d1	ENSRNOG00000002180

Paralogs (45): RABGAP1 (ENSG00000011454), TBC1D22A (ENSG00000054611), TBC1D22B (ENSG00000065491), EVI5 (ENSG00000067208), TBC1D25 (ENSG00000068354), TBC1D2 (ENSG00000095383), TBC1D10A (ENSG00000099992), SGSM3 (ENSG00000100359), TBC1D17 (ENSG00000104946), TBC1D13 (ENSG00000107021), TBC1D12 (ENSG00000108239), TBC1D9 (ENSG00000109436), TBC1D30 (ENSG00000111490), TBC1D15 (ENSG00000121749), TBC1D5 (ENSG00000131374), TBC1D14 (ENSG00000132405), TBC1D8B (ENSG00000133138), TBC1D4 (ENSG00000136111), GRTP1 (ENSG00000139835), SGSM2 (ENSG00000141258), EVI5L (ENSG00000142459), TBCK (ENSG00000145348), USP6NL (ENSG00000148429), RABGAP1L (ENSG00000152061), SGSM1 (ENSG00000167037), TBC1D21 (ENSG00000167139), TBC1D2B (ENSG00000167202), TBC1D16 (ENSG00000167291), TBC1D10B (ENSG00000169221), TBC1D10C (ENSG00000175463), TBC1D28 (ENSG00000189375), TBC1D9B (ENSG00000197226), TBC1D8 (ENSG00000204634), TBC1D26 (ENSG00000214946), TBC1D3G (ENSG00000260287), TBC1D3K (ENSG00000273513), TBC1D3H (ENSG00000274226), TBC1D3D (ENSG00000274419), TBC1D3L (ENSG00000274512), TBC1D3 (ENSG00000274611)

Protein

Protein identifiers

TBC1 domain family member 1 — Q86TI0 (reviewed: Q86TI0)

All UniProt accessions (9): Q86TI0, A0A8V8TNS9, B5MCJ2, B9A6J6, C9JIE2, H0Y8P0, H0YA01, H7C0Z7, H7C380

UniProt curated annotations — full annotation on UniProt →

Function. May act as a GTPase-activating protein for Rab family protein(s). May play a role in the cell cycle and differentiation of various tissues. Involved in the trafficking and translocation of GLUT4-containing vesicles and insulin-stimulated glucose uptake into cells.

Subunit / interactions. Interacts with APPL2 (via BAR domain); interaction is dependent of TBC1D1 phosphorylation at Ser-235; interaction diminishes the phosphorylation of TBC1D1 at Thr-596, resulting in inhibition of SLC2A4/GLUT4 translocation and glucose uptake.

Subcellular location. Nucleus.

Post-translational modifications. Insulin-stimulated phosphorylation by AKT family kinases stimulates SLC2A4/GLUT4 translocation.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86TI0-1	1	yes
Q86TI0-2	2

RefSeq proteins (3): NP_001240841, NP_001383888, NP_055988 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000195	Rab-GAP-TBC_dom	Domain
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR021785	DUF3350	Domain
IPR035969	Rab-GAP_TBC_sf	Homologous_superfamily
IPR050302	Rab_GAP_TBC_domain	Family

Pfam: PF00566, PF00640, PF11830

UniProt features (72 total): helix 22, modified residue 20, region of interest 6, sequence variant 6, turn 5, compositionally biased region 3, domain 2, splice variant 2, mutagenesis site 2, sequence conflict 2, chain 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3QYE	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86TI0-F1	71.31	0.36

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 (20): 146, 235, 237, 503, 505, 507, 525, 527, 565, 566, 570, 571, 585, 596, 614, 627, 695, 941, 952, 1131

Mutagenesis-validated functional residues (2):

Position	Phenotype
930	substantially reduced rabgap gtpase hydrolysis activity.
1019	substantially reduced rabgap gtpase hydrolysis activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-199991	Membrane Trafficking
R-HSA-5653656	Vesicle-mediated transport

MSigDB gene sets: 252 (showing top): GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, REACTOME_MEMBRANE_TRAFFICKING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GTGCCTT_MIR506, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, ONKEN_UVEAL_MELANOMA_UP, MODULE_239, FOSTER_TOLERANT_MACROPHAGE_UP, GOBP_CILIUM_ORGANIZATION, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_DN, MARTIN_VIRAL_GPCR_SIGNALING_DN, GOBP_ORGANELLE_ASSEMBLY, SCHLOSSER_SERUM_RESPONSE_DN, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN

GO Biological Process (2): regulation of protein localization (GO:0032880), negative regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0061179)

GO Molecular Function (2): GTPase activator activity (GO:0005096), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), Golgi apparatus (GO:0005794), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Membrane Trafficking	1
Vesicle-mediated transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
intracellular protein localization	1
regulation of localization	1
insulin secretion involved in cellular response to glucose stimulus	1
negative regulation of insulin secretion	1
negative regulation of response to stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1086 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBC1D1	CDC16	Q13042	846
TBC1D1	SLC2A4	P14672	761
TBC1D1	RASA1	P20936	748
TBC1D1	CCKAR	P32238	691
TBC1D1	RAB10	P61026	622
TBC1D1	ZFP69	Q49AA0	620
TBC1D1	INS	P01308	598
TBC1D1	TBC1D21	Q8IYX1	566
TBC1D1	RAB8A	P24407	558
TBC1D1	RAB35	Q15286	518
TBC1D1	TBC1D13	Q9NVG8	506
TBC1D1	NBPF1	Q3BBV0	502
TBC1D1	CDK11B	P21127	493
TBC1D1	AKT1	P31749	488
TBC1D1	TBC1D16	Q8TBP0	487

IntAct

148 interactions, top by confidence:

A	B	Type	Score
YWHAG	TBC1D1	psi-mi:“MI:0915”(physical association)	0.820
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
TNNC2	TBC1D1	psi-mi:“MI:0915”(physical association)	0.670
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
APPL2	TBC1D1	psi-mi:“MI:0915”(physical association)	0.580
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
HOXC8	TBC1D1	psi-mi:“MI:0915”(physical association)	0.560
TXLNA	TBC1D1	psi-mi:“MI:0915”(physical association)	0.560
TBC1D1	VPS52	psi-mi:“MI:0915”(physical association)	0.560
HSF2BP	TBC1D1	psi-mi:“MI:0915”(physical association)	0.560
TBC1D1	LNX1	psi-mi:“MI:0915”(physical association)	0.560
TBC1D1	L3MBTL3	psi-mi:“MI:0915”(physical association)	0.560
TBC1D1	FAM50B	psi-mi:“MI:0915”(physical association)	0.560
	TBC1D1	psi-mi:“MI:0915”(physical association)	0.560
CWF19L2	TBC1D1	psi-mi:“MI:0915”(physical association)	0.560
TBC1D1	LZTS1	psi-mi:“MI:0915”(physical association)	0.560
TBC1D1	MCRS1	psi-mi:“MI:0915”(physical association)	0.560
RIN1	TBC1D1	psi-mi:“MI:0915”(physical association)	0.560
TBC1D1	GMCL1	psi-mi:“MI:0915”(physical association)	0.560
FAM161A	TBC1D1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (92): Rab14 (Co-crystal Structure), Rab14 (Biochemical Activity), TBC1D1 (Two-hybrid), TBC1D1 (Affinity Capture-MS), TBC1D1 (Affinity Capture-MS), KIF13B (Affinity Capture-MS), TBC1D1 (Affinity Capture-MS), TBC1D1 (Affinity Capture-MS), CGN (Affinity Capture-MS), GIGYF1 (Affinity Capture-MS), CBY1 (Affinity Capture-MS), TBC1D1 (Affinity Capture-RNA), TBC1D1 (Affinity Capture-RNA), TBC1D1 (Proximity Label-MS), TBC1D1 (Affinity Capture-RNA)

ESM2 similar proteins: A0FGR9, A2AP18, A3KGF7, A5D6R3, F8VPU2, O14976, O15068, O43304, O75038, O89040, O94887, P10688, P10895, P19687, P21671, P33402, P51178, P51432, P97874, Q00722, Q01970, Q0V9N0, Q15111, Q3U5C8, Q3USB7, Q4KWH5, Q4KWH8, Q4R6L3, Q5QNQ6, Q5RAB8, Q5RJH2, Q5SVR0, Q62688, Q62711, Q63406, Q64096, Q66K14, Q69Z98, Q86TI0, Q8IWQ3

Diamond homologs: A0A087WVF3, A0A087WXS9, A0A087X179, A0A087X1G2, A2AWA9, A3KGB4, A6H6A9, A6NDS4, A6NER0, A6QP29, B0R0W9, B7ZAP0, B9A6J9, H2KZZ6, O60343, O60447, O95759, O97790, P0C7X1, P35125, P58802, P97366, Q0IIM8, Q10496, Q12317, Q12344, Q28CB1, Q3UYK3, Q4KMP7, Q5R372, Q5RAN1, Q5RCW6, Q5SVR0, Q5TC63, Q5ZJ17, Q60949, Q66K14, Q6DHY5, Q6IPX1, Q6ZT07

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKAA1	down-regulates	TBC1D1	phosphorylation
AMPK	down-regulates	TBC1D1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 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	7	98.7×	5e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	87.1×	8e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	87.1×	8e-11
Activation of BH3-only proteins	7	64.4×	6e-10
FOXO-mediated transcription	7	43.5×	1e-08
RHO GTPases activate PKNs	7	41.1×	1e-08
Intrinsic Pathway for Apoptosis	7	38.0×	2e-08
Translocation of SLC2A4 (GLUT4) to the plasma membrane	10	28.6×	1e-10

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	7	35.1×	3e-07
substantia nigra development	6	30.1×	8e-06
intracellular protein localization	8	11.5×	7e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	170
Likely benign	44
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

5966 predictions. Top by Δscore:

Variant	Effect	Δscore
4:37891345:ACAGG:A	donor_loss	1.0000
4:37891346:CAGG:C	donor_loss	1.0000
4:37891348:GGTAA:G	donor_loss	1.0000
4:37891349:G:C	donor_loss	1.0000
4:37891350:T:A	donor_loss	1.0000
4:37901997:CCCCA:C	acceptor_loss	1.0000
4:37901998:CCCA:C	acceptor_loss	1.0000
4:37901999:CCA:C	acceptor_loss	1.0000
4:37902000:CA:C	acceptor_loss	1.0000
4:37902001:A:AC	acceptor_loss	1.0000
4:37902002:G:A	acceptor_loss	1.0000
4:37902513:G:GG	donor_gain	1.0000
4:38014506:CAG:C	acceptor_loss	1.0000
4:38014507:A:AG	acceptor_gain	1.0000
4:38014507:AG:A	acceptor_gain	1.0000
4:38014507:AGG:A	acceptor_loss	1.0000
4:38014507:AGGT:A	acceptor_gain	1.0000
4:38014508:G:A	acceptor_loss	1.0000
4:38014508:G:GA	acceptor_gain	1.0000
4:38014508:GG:G	acceptor_gain	1.0000
4:38014508:GGT:G	acceptor_gain	1.0000
4:38014508:GGTG:G	acceptor_gain	1.0000
4:38014508:GGTGC:G	acceptor_gain	1.0000
4:38018352:A:G	acceptor_gain	1.0000
4:38020741:G:GT	donor_gain	1.0000
4:38020742:A:T	donor_gain	1.0000
4:38021582:TTA:T	acceptor_loss	1.0000
4:38021583:TAG:T	acceptor_loss	1.0000
4:38021585:G:GT	acceptor_loss	1.0000
4:38021585:GGTT:G	acceptor_gain	1.0000

AlphaMissense

8354 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:38014969:T:C	F293S	1.000
4:38020591:G:C	G325R	1.000
4:38020615:G:T	G333W	1.000
4:38020616:G:A	G333E	1.000
4:38020619:T:C	F334S	1.000
4:38020680:C:G	C354W	1.000
4:38054269:T:A	W661R	1.000
4:38054269:T:C	W661R	1.000
4:38103146:T:C	L849P	1.000
4:38014618:T:C	L176P	0.999
4:38014669:T:A	I193N	0.999
4:38014671:G:C	D194H	0.999
4:38018376:T:C	L302P	0.999
4:38018427:T:A	I319K	0.999
4:38020592:G:A	G325D	0.999
4:38020592:G:T	G325V	0.999
4:38020610:A:C	H331P	0.999
4:38020613:T:C	F332S	0.999
4:38020615:G:A	G333R	0.999
4:38020615:G:C	G333R	0.999
4:38020663:T:C	C349R	0.999
4:38020665:T:G	C349W	0.999
4:38020670:T:A	V351E	0.999
4:38020673:T:C	F352S	0.999
4:38020678:T:C	C354R	0.999
4:38020679:G:A	C354Y	0.999
4:38021608:T:C	L367P	0.999
4:38027818:T:C	L414P	0.999
4:38054271:G:C	W661C	0.999
4:38054271:G:T	W661C	0.999

dbSNP variants (sampled 300 via entrez): RS1000009219 (4:37974365 A>G), RS1000030671 (4:37980048 G>T), RS1000036706 (4:37980505 G>A), RS1000037923 (4:37928987 A>G), RS1000057466 (4:38016452 C>G,T), RS1000080845 (4:37974371 C>G), RS1000086240 (4:38006683 G>A,T), RS1000096991 (4:38065830 A>G), RS1000112634 (4:37905758 T>A,C), RS10001208 (4:38102407 G>A), RS1000126685 (4:38065961 C>A,G,T), RS1000133181 (4:37974071 G>A), RS1000135210 (4:37929808 A>G), RS1000141893 (4:38028818 A>G), RS10001462 (4:38072565 G>A)

Disease associations

OMIM: gene MIM:609850 | disease phenotypes: MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
non-syndromic renal or urinary tract malformation	Strong	Autosomal dominant
congenital anomaly of kidney and urinary tract	Limited	Autosomal dominant

Mondo (2): congenital anomaly of kidney and urinary tract (MONDO:0019719), (MONDO:0019720)

Orphanet (2): Non-syndromic renal or urinary tract malformation (Orphanet:93546), Renal or urinary tract malformation (Orphanet:93545)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST001588_16	Periodontal microbiota	4.000000e-06
GCST001785_2	Crohn’s disease	1.000000e-11
GCST002094_3	Crohn’s disease	4.000000e-14
GCST002337_107	Amyotrophic lateral sclerosis (sporadic)	7.000000e-07
GCST002701_11	Verbal declarative memory	4.000000e-06
GCST004627_53	Lymphocyte count	2.000000e-15
GCST004632_100	Lymphocyte percentage of white cells	3.000000e-11
GCST004633_118	Neutrophil percentage of white cells	5.000000e-09
GCST004793_4	Amyotrophic lateral sclerosis in C9orf72 mutation negative individuals	3.000000e-06
GCST006258_6	Diastolic blood pressure	4.000000e-09
GCST006259_36	Systolic blood pressure	2.000000e-14
GCST007060_7	Response to SSRI (symptom remission)	2.000000e-06
GCST007061_7	Response to antidepressants (symptom remission)	3.000000e-06
GCST007094_83	Diastolic blood pressure	2.000000e-07
GCST007095_68	Systolic blood pressure	4.000000e-06
GCST007096_186	Pulse pressure	3.000000e-09
GCST007099_241	Systolic blood pressure	4.000000e-13
GCST008152_183	Weight	8.000000e-06
GCST011961_2	High-sensitivity cardiac troponin T levels	2.000000e-06
GCST012306_2	Bipolar disorder	7.000000e-06
GCST90002388_209	Lymphocyte count	5.000000e-44
GCST90002389_39	Lymphocyte percentage of white cells	1.000000e-24
GCST90002394_51	Monocyte percentage of white cells	3.000000e-10
GCST90002399_415	Neutrophil percentage of white cells	2.000000e-16
GCST90002407_426	White blood cell count	6.000000e-09
GCST90006995_6	Gut microbiota relative abundance (unclassified genus belonging to family Lachnospiraceae)	5.000000e-06

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0005763	pulse pressure measurement
EFO:0004338	body weight
EFO:0005043	cardiac troponin T measurement
EFO:0007989	monocyte percentage of leukocytes
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566906	Cakut (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs9852	Toxicity	3	clozapine;olanzapine	Schizophrenia

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs9852	TBC1D1	3	2.00	1	clozapine;olanzapine
rs35859249	TBC1D1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	7
Benzo(a)pyrene	decreases expression, increases methylation	3
bisphenol A	decreases expression, increases methylation	2
Air Pollutants	increases oxidation, affects expression, affects cotreatment, increases abundance	2
Nickel	increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	2
Tretinoin	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
trichostatin A	increases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases methylation	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Calcitriol	increases expression, affects cotreatment	1
Curcumin	decreases expression	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Estradiol	affects cotreatment, increases expression, decreases expression	1
Formaldehyde	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)