TBC1D4

Summary

TBC1D4 (TBC1 domain family member 4, HGNC:19165) is a protein-coding gene on chromosome 13q22.2, encoding TBC1 domain family member 4 (O60343). May act as a GTPase-activating protein for RAB2A, RAB8A, RAB10 and RAB14.

This gene is a member of the Tre-2/BUB2/CDC16 domain family. The protein encoded by this gene is a Rab-GTPase-activating protein, and contains two phopshotyrosine-binding domains (PTB1 and PTB2), a calmodulin-binding domain (CBD), a Rab-GTPase domain, and multiple AKT phosphomotifs. This protein is thought to play an important role in glucose homeostasis by regulating the insulin-dependent trafficking of the glucose transporter 4 (GLUT4), important for removing glucose from the bloodstream into skeletal muscle and fat tissues. Reduced expression of this gene results in an increase in GLUT4 levels at the plasma membrane, suggesting that this protein is important in intracellular retention of GLUT4 under basal conditions. When exposed to insulin, this protein is phosphorylated, dissociates from GLUT4 vesicles, resulting in increased GLUT4 at the cell surface, and enhanced glucose transport. Phosphorylation of this protein by AKT is required for proper translocation of GLUT4 to the cell surface. Individuals homozygous for a mutation in this gene are at higher risk for type 2 diabetes and have higher levels of circulating glucose and insulin levels after glucose ingestion. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 9882 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 246 total
• MANE Select transcript: NM_014832

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19165
Approved symbol	TBC1D4
Name	TBC1 domain family member 4
Location	13q22.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0603, AS160, DKFZp779C0666
Ensembl gene	ENSG00000136111
Ensembl biotype	protein_coding
OMIM	612465
Entrez	9882

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000377625, ENST00000377636, ENST00000413735, ENST00000431480, ENST00000478591, ENST00000488955, ENST00000493487, ENST00000648194, ENST00000881333, ENST00000954254, ENST00000954255, ENST00000954256, ENST00000954257, ENST00000954258

RefSeq mRNA: 3 — MANE Select: NM_014832 NM_001286658, NM_001286659, NM_014832

CCDS: CCDS41901, CCDS66563, CCDS66564

Canonical transcript exons

ENST00000377636 — 21 exons

Exon	Start	End
ENSE00001692326	75292102	75292271
ENSE00001728280	75294854	75295013
ENSE00001757251	75306313	75306471
ENSE00001762024	75288934	75289110
ENSE00003484499	75326197	75326423
ENSE00003522821	75362026	75362607
ENSE00003523207	75320014	75320037
ENSE00003541756	75336921	75337040
ENSE00003560931	75312738	75312898
ENSE00003569387	75302243	75302401
ENSE00003572650	75324237	75324401
ENSE00003594236	75309942	75310151
ENSE00003608901	75359769	75359858
ENSE00003610261	75341125	75341235
ENSE00003625372	75349170	75349302
ENSE00003631158	75341496	75341587
ENSE00003638280	75327752	75327826
ENSE00003673887	75356147	75356251
ENSE00003686007	75299330	75299574
ENSE00003833139	75283503	75287025
ENSE00003893703	75481270	75482169

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 98.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.4755 / max 355.5049, expressed in 1633 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137646	3.1195	1243
137638	1.9780	260
137647	1.0317	544
137645	0.8816	454
137649	0.6537	342
137644	0.4509	261
137648	0.3985	191
137643	0.3014	167
137631	0.2923	76
137636	0.2670	78

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.32	gold quality
renal medulla	UBERON:0000362	97.99	gold quality
diaphragm	UBERON:0001103	97.51	gold quality
vastus lateralis	UBERON:0001379	96.83	gold quality
parotid gland	UBERON:0001831	96.70	gold quality
quadriceps femoris	UBERON:0001377	96.62	gold quality
skeletal muscle tissue	UBERON:0001134	96.58	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.52	gold quality
adrenal tissue	UBERON:0018303	96.41	gold quality
caput epididymis	UBERON:0004358	96.16	gold quality
biceps brachii	UBERON:0001507	96.13	gold quality
muscle tissue	UBERON:0002385	95.52	gold quality
corpus epididymis	UBERON:0004359	95.49	gold quality
right adrenal gland cortex	UBERON:0035827	95.47	gold quality
adrenal cortex	UBERON:0001235	95.42	gold quality
right adrenal gland	UBERON:0001233	95.36	gold quality
left adrenal gland	UBERON:0001234	95.22	gold quality
triceps brachii	UBERON:0001509	95.13	gold quality
left adrenal gland cortex	UBERON:0035825	95.09	gold quality
deltoid	UBERON:0001476	95.05	gold quality
gluteal muscle	UBERON:0002000	95.04	gold quality
epithelium of mammary gland	UBERON:0003244	94.96	gold quality
adrenal gland	UBERON:0002369	94.94	gold quality
muscle organ	UBERON:0001630	94.93	gold quality
body of tongue	UBERON:0011876	94.86	gold quality
tongue	UBERON:0001723	94.80	gold quality
mammary duct	UBERON:0001765	94.69	gold quality
superior surface of tongue	UBERON:0007371	94.59	gold quality
gastrocnemius	UBERON:0001388	94.44	gold quality
left ventricle myocardium	UBERON:0006566	94.44	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-MTAB-8498	yes	3258.90
E-MTAB-7381	yes	1240.48
E-CURD-95	yes	285.04
E-MTAB-8271	yes	283.27
E-MTAB-8142	yes	82.69
E-CURD-119	yes	54.71
E-CURD-120	yes	33.35
E-CURD-88	yes	30.58
E-HCAD-35	yes	20.20
E-CURD-46	yes	19.52
E-HCAD-1	yes	11.04
E-HCAD-29	no	848.99
E-CURD-89	no	743.53
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

170 targeting TBC1D4, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4531	99.99	69.70	3181
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-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562

Literature-anchored findings (GeneRIF, showing 37)

• KIAA0603 is likely to be a Rab GAP that participates in the regulation of activated T cells in atopic dermatitis (PMID:15304337)
• In this study, we determined the expression of and in vivo insulin action on AS160 in skeletal muscle of normal and type 2 diabetic patients. (PMID:15919790)
• results indicate that AS160 is a Rab GAP, and suggest novel Rabs that may participate in GLUT4 translocation (PMID:15971998)
• AS160 is phosphorylated in a time-dependent manner during moderate-intensity exercise. (PMID:17077344)
• Regulation of AS160 and interaction with 14-3-3 in skeletal muscle are influenced by resistance exercise and insulin but do not fully explain the effect of resistance exercise on whole-body insulin action. (PMID:17369524)
• Effects of endurance exercise training on insulin signaling and AS160 in human skeletal muscle (PMID:17513702)
• AS160 is a common target of insulin, IGF-1, EGF, PMA and AICAR, these stimuli induce distinctive patterns of phosphorylation and 14-3-3 binding, mediated by at least four protein kinases. (PMID:17617058)
• Impaired insulin signaling through Akt and AS160 in part explains insulin resistance at the molecular level in skeletal muscle in polycystic ovary syndrome. (PMID:17977950)
• AS160, previously recognized as a key player in insulin signaling in skeletal muscle and adipose tissue, is also a major effector of protein kinase B/Akt signaling in the beta-cell. (PMID:18276765)
• The transcript variant 2 of AS160 in contrast to full-length AS160 is a novel regulator of glucose transport that positively influences glucose-uptake rates. (PMID:18771725)
• muscle TBC1D4 phosphorylation across the leg is increased during recovery following resistance exercise (PMID:18845784)
• Specific phosphorylation of TBC1D4 in human skeletal muscle in response to physiological exercise-induced hyperinsulinemia. (PMID:19252894)
• Prematurely truncated TBC1D4 protein tended to increase basal cell membrane GLUT4 levels (P = 0.053) and significantly reduced insulin-stimulated GLUT4 cell membrane translocation (P < 0.05). (PMID:19470471)
• S711 is a novel TBC1D4 phosphorylation site regulated by AMPK in skeletal muscle. (PMID:19923418)
• results show AS160 phosphorylation level is frequently increased in breast cancer; results implicate a possible role of AS160 in breast tumorigenesis and suggest that p-AS160 might be useful as a marker and a potential novel treatment target (PMID:20574165)
• WNK1 promotes cell surface expression of glucose transporter GLUT1 by regulating a Tre-2/USP6-BUB2-Cdc16 domain family member 4 (TBC1D4)-Rab8A complex (PMID:20937822)
• Impaired insulin-induced site-specific TBC1D4 phosphorylation may contribute to skeletal muscle insulin resistance in type 2 diabetes. (PMID:20938636)
• AS160 interacts with the large cytoplasmic NP domain of the alpha-subunit of the Na(+),K(+)-ATPase. AMP-stimulated protein kinase (AMPK) and AS160 participate in a common pathway to modulate the cell surface expression of the Na(+),K(+)-ATPase. (PMID:20943949)
• Crystal structures of human TBC1D1 and TBC1D4 (AS160) RabGTPase-activating protein (RabGAP) domains reveal critical elements for GLUT4 translocation. (PMID:21454505)
• AS160 phosphotyrosine-binding domain constructs inhibit insulin-stimulated GLUT4 vesicle fusion with the plasma membrane (PMID:21454690)
• insulin resistance in muscles from healthy individuals is associated with suppression of site-specific phosphorylation of AS160 (PMID:22028408)
• Findings suggest that a dampening of insulin-induced phosphorylation of AS160 on specific sites in skeletal muscle contributes to the insulin resistance evident in a sedentary aging population (PMID:23801578)
• AS160 and TBC1D1 phosphorylations were evident 30 min after exercise. (PMID:24876356)
• The long isoform of TBC1D4 is primarily expressed in skeletal muscle. Decreased protein abundance of the long isoform and of the mRNA encoding it in individuals carrying one or two copies of the TBC1D4 p.Arg684Ter allele is correlated with increased plasma glucose levels and increased frequency of T2D. (PMID:25043022)
• homozygous carriers of a nonsense p.Arg684Ter variant have markedly higher concentrations of plasma glucose and serum insulin 2 hours after an oral glucose load compared with individuals with other genotypes (PMID:25043022)
• AS160 regulates glucose-independent eukaryotic cell proliferation through p21-dependent control of the cell cycle. (PMID:27152871)
• Disruption of TBC1D4 is common among North American Inuit, resulting in exclusively elevated postprandial glucose. This leads to underdiagnosis of type 2 diabetes, unless an OGTT is performed. (PMID:27561922)
• C-terminal region (CTR) region is largely alpha-helical and mediates TBC1D4 RabGAP dimerization (PMID:28545963)
• Sex and fiber type independently influence AMPK, TBC1D1, and TBC1D4 at rest and during recovery from high-intensity exercise in humans. (PMID:31895596)
• Tankyrase inhibition augments neuronal insulin sensitivity and glucose uptake via AMPK-AS160 mediated pathway. (PMID:33002563)
• The effect of diabetes and the common diabetogenic TBC1D4 p.Arg684Ter variant on cardiovascular risk in Inuit in Greenland. (PMID:33328529)
• Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers. (PMID:33912980)
• 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)
• Transporters, TBC1D4, and ARID5B Variants to Explain Glycated Hemoglobin Variability in Patients with Type 2 Diabetes. (PMID:34265779)
• The effect of diabetes and the diabetogenic TBC1D4 p.Arg684ter variant on kidney function in Inuit in Greenland. (PMID:36944026)
• The effect of traditional diet on glucose homoeostasis in carriers and non-carriers of a common TBC1D4 variant in Greenlandic Inuit: a randomised crossover study. (PMID:37129117)
• Expression characteristics of TBC1D4 activating protein molecule and identification of key module genes for preventing thyroid cancer progression. (PMID:39181362)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbc1d4	ENSDARG00000075156
mus_musculus	Tbc1d4	ENSMUSG00000033083
rattus_norvegicus	Tbc1d4	ENSRNOG00000009431

Paralogs (45): RABGAP1 (ENSG00000011454), TBC1D22A (ENSG00000054611), TBC1D22B (ENSG00000065491), TBC1D1 (ENSG00000065882), 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), 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 4 — O60343 (reviewed: O60343)

Alternative names: Akt substrate of 160 kDa

All UniProt accessions (3): A0A3B3IRT3, O60343, Q5JU47

UniProt curated annotations — full annotation on UniProt →

Function. May act as a GTPase-activating protein for RAB2A, RAB8A, RAB10 and RAB14. Isoform 2 promotes insulin-induced glucose transporter SLC2A4/GLUT4 translocation at the plasma membrane, thus increasing glucose uptake.

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed. Isoform 2 is the highest overexpressed in most tissues. Isoform 1 is highly expressed in skeletal muscle and heart, but was not detectable in the liver nor in adipose tissue. Isoform 2 is strongly expressed in adrenal and thyroid gland, and also in lung, kidney, colon, brain and adipose tissue. Isoform 2 is moderately expressed in skeletal muscle. Expressed in pancreatic Langerhans islets, including beta cells (at protein level). Expression is decreased by twofold in pancreatic islets in type 2 diabetes patients compared to control subjects. Up-regulated in T-cells from patients with atopic dermatitis.

Post-translational modifications. Phosphorylated by AKT1; insulin-induced. Also phosphorylated by AMPK in response to insulin. Insulin-stimulated phosphorylation is required for SLC2A4/GLUT4 translocation. Has no effect on SLC2A4/GLUT4 internalization. Physiological hyperinsulinemia increases phosphorylation in skeletal muscle. Insulin-stimulated phosphorylation is reduced by 39% in type 2 diabetic patients.

Disease relevance. Type 2 diabetes mellitus 5 (T2D5) [MIM:616087] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Isoforms (5)

UniProt ID	Names	Canonical?
O60343-1	1	yes
O60343-2	2, AS160_tv2
O60343-3	3, AS160_tv3
O60343-4	4
O60343-5	5

RefSeq proteins (3): NP_001273587, NP_001273588, NP_055647* (*=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 (85 total): modified residue 25, helix 17, turn 9, sequence variant 6, sequence conflict 6, region of interest 5, mutagenesis site 5, splice variant 4, domain 3, compositionally biased region 3, chain 1, strand 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7NIX	X-RAY DIFFRACTION	1.9
3QYB	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60343-F1	67.76	0.31

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 (25): 1, 262, 314, 318, 341, 344, 477, 566, 568, 570, 577, 588, 591, 609, 613, 617, 642, 666, 751, 754 …

Mutagenesis-validated functional residues (5):

Position	Phenotype
318	80% reduction of insulin-stimulated glut4 translocation; when associated with a-588; a-642 and a-751.
588	80% reduction of insulin-stimulated glut4 translocation; when associated with a-318; a-642 and a-751.
642	80% reduction of insulin-stimulated glut4 translocation; when associated with a-318; a-588 and a-751.
751	80% reduction of insulin-stimulated glut4 translocation; when associated with a-318; a-588 and a-642.
972	loss of rab gtpase activation. only 20% reduction of glut4 translocation; even when associated with a-318; a-588; a-642

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: 300 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOBP_RESPONSE_TO_INSULIN, MODULE_206, DELYS_THYROID_CANCER_DN, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, LEE_EARLY_T_LYMPHOCYTE_DN, GOBP_CELLULAR_RESPONSE_TO_NITROGEN_COMPOUND

GO Biological Process (3): vesicle-mediated transport (GO:0016192), negative regulation of vesicle fusion (GO:0031339), cellular response to insulin stimulus (GO:0032869)

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

GO Cellular Component (4): Golgi apparatus (GO:0005794), cytosol (GO:0005829), vesicle (GO:0031982), 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
cytoplasm	2
cellular anatomical structure	2
transport	1
cellular process	1
vesicle fusion	1
negative regulation of organelle organization	1
regulation of vesicle fusion	1
negative regulation of transport	1
response to insulin	1
cellular response to peptide hormone stimulus	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1298 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBC1D4	SLC2A4	P14672	969
TBC1D4	AKT2	P31751	946
TBC1D4	RAB10	P61026	911
TBC1D4	RAB14	P35287	909
TBC1D4	RAB8A	P24407	872
TBC1D4	RASA1	P20936	857
TBC1D4	INS	P01308	855
TBC1D4	AKT1	P31749	810
TBC1D4	LNPEP	Q9UIQ6	792
TBC1D4	IRS1	P35568	728
TBC1D4	RAB11A	P24410	721
TBC1D4	RAB2A	P08886	720
TBC1D4	PHLPP1	O60346	702
TBC1D4	CALML6	Q8TD86	636
TBC1D4	CALML3	P27482	636
TBC1D4	YWHAZ	P29213	636

IntAct

135 interactions, top by confidence:

A	B	Type	Score
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
TBC1D4	YWHAZ	psi-mi:“MI:0915”(physical association)	0.790
TBC1D4	YWHAE	psi-mi:“MI:0915”(physical association)	0.690
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
ZNF414	AHCYL1	psi-mi:“MI:0914”(association)	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
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
MIS12	SPC24	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
FAM9B	GEMIN2	psi-mi:“MI:0914”(association)	0.530
NRBP1	TBC1D4	psi-mi:“MI:0914”(association)	0.530
EMILIN1	METTL15	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
SFN	TBC1D4	psi-mi:“MI:0915”(physical association)	0.470
TBC1D4	H1-2	psi-mi:“MI:0915”(physical association)	0.400
UPP1	TBC1D4	psi-mi:“MI:0915”(physical association)	0.400
TBC1D4	CDC42	psi-mi:“MI:0915”(physical association)	0.370
TBC1D4	TOPBP1	psi-mi:“MI:0915”(physical association)	0.370
TBC1D4	KATNIP	psi-mi:“MI:0915”(physical association)	0.370
TBC1D4	NFAT5	psi-mi:“MI:0915”(physical association)	0.370
TBC1D4	TASOR	psi-mi:“MI:0915”(physical association)	0.370
TBC1D4	NAV1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (186): TBC1D4 (Affinity Capture-Western), TBC1D4 (Affinity Capture-MS), TBC1D4 (Affinity Capture-MS), Rab14 (Co-crystal Structure), Rab14 (Biochemical Activity), TBC1D4 (Affinity Capture-MS), TBC1D4 (Affinity Capture-MS), TBC1D4 (Affinity Capture-MS), TBC1D4 (Affinity Capture-MS), TBC1D4 (Affinity Capture-MS), TBC1D4 (Affinity Capture-MS), TBC1D4 (Affinity Capture-Western), TBC1D4 (Affinity Capture-Western), TBC1D4 (Biochemical Activity), TBC1D4 (Affinity Capture-MS)

ESM2 similar proteins: A2AR50, B0UXH6, D3ZAZ5, D4AB98, F1M386, F1MSG6, F1PBJ0, F7EL49, O60343, O75044, O97790, P0CE43, P42331, Q00IB7, Q13905, Q14155, Q15678, Q28CB1, Q4R7W3, Q58DL5, Q5JS13, Q5U2Z7, Q5ZJK0, Q60695, Q60949, Q62130, Q62136, Q6INE5, Q6INP9, Q6P112, Q6P549, Q7Z6B7, Q80TI1, Q86TI0, Q86X27, Q8BYJ6, Q8BYW1, Q8C4V1, Q8CHG7, Q8IV61

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

7 interactions.

A	Effect	B	Mechanism
AKT	unknown	TBC1D4	phosphorylation
AKT1	unknown	TBC1D4	phosphorylation
AKT1	down-regulates	TBC1D4	phosphorylation
AKT2	“down-regulates activity”	TBC1D4	phosphorylation
AKT	down-regulates	TBC1D4	phosphorylation
TBC1D4	down-regulates	SLC2A4

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 130 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	8	59.7×	5e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	59.7×	5e-11
Activation of BAD and translocation to mitochondria	7	59.2×	1e-09
Activation of BH3-only proteins	7	38.6×	3e-08
RHO GTPases activate PKNs	8	28.2×	3e-08
Intrinsic Pathway for Apoptosis	7	22.8×	1e-06
RAF activation	5	18.7×	1e-04
FOXO-mediated transcription	5	18.7×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
substantia nigra development	7	22.1×	1e-05
protein targeting	5	15.8×	2e-03
G2/M transition of mitotic cell cycle	5	13.4×	4e-03
intracellular protein localization	9	8.1×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	161
Likely benign	11
Benign	47

Top pathogenic / likely-pathogenic (0)

SpliceAI

4247 predictions. Top by Δscore:

Variant	Effect	Δscore
13:75288929:TTTA:T	donor_loss	1.0000
13:75288930:TTACC:T	donor_loss	1.0000
13:75288931:TAC:T	donor_loss	1.0000
13:75288932:A:AT	donor_loss	1.0000
13:75288933:C:CG	donor_loss	1.0000
13:75289112:T:C	acceptor_loss	1.0000
13:75292096:TCATA:T	donor_loss	1.0000
13:75292097:CATA:C	donor_loss	1.0000
13:75292098:ATACC:A	donor_loss	1.0000
13:75292099:TACC:T	donor_loss	1.0000
13:75292101:C:CA	donor_loss	1.0000
13:75292267:AATAT:A	acceptor_gain	1.0000
13:75292269:TAT:T	acceptor_gain	1.0000
13:75292271:TC:T	acceptor_loss	1.0000
13:75292272:C:CC	acceptor_gain	1.0000
13:75299324:CCTCA:C	donor_loss	1.0000
13:75299325:CTCA:C	donor_loss	1.0000
13:75299327:CA:C	donor_loss	1.0000
13:75299329:CC:C	donor_loss	1.0000
13:75302238:CATA:C	donor_loss	1.0000
13:75302239:ATAC:A	donor_loss	1.0000
13:75302240:TA:T	donor_loss	1.0000
13:75302241:AC:A	donor_loss	1.0000
13:75302399:CTC:C	acceptor_gain	1.0000
13:75302400:TCC:T	acceptor_loss	1.0000
13:75302402:CTA:C	acceptor_loss	1.0000
13:75302403:T:C	acceptor_loss	1.0000
13:75307490:T:TA	donor_gain	1.0000
13:75309936:GCTAA:G	donor_loss	1.0000
13:75309937:CTAAC:C	donor_loss	1.0000

AlphaMissense

8557 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:75288950:A:G	L1216P	1.000
13:75294911:A:G	W1087R	1.000
13:75294911:A:T	W1087R	1.000
13:75294985:A:G	L1062P	1.000
13:75294988:A:G	L1061P	1.000
13:75294991:C:A	R1060M	1.000
13:75294991:C:G	R1060T	1.000
13:75294997:A:G	L1058P	1.000
13:75299450:G:C	S1012R	1.000
13:75299450:G:T	S1012R	1.000
13:75299452:T:G	S1012R	1.000
13:75359836:A:G	L368P	1.000
13:75362030:A:G	F359S	1.000
13:75362033:A:G	L358P	1.000
13:75481292:A:G	F159S	1.000
13:75481295:A:T	V158D	1.000
13:75481599:A:G	W57R	1.000
13:75481599:A:T	W57R	1.000
13:75288971:A:G	L1209P	0.999
13:75289052:A:G	L1182P	0.999
13:75289062:A:C	Y1179D	0.999
13:75294919:G:T	A1084D	0.999
13:75294927:A:C	S1081R	0.999
13:75294927:A:T	S1081R	0.999
13:75294929:T:G	S1081R	0.999
13:75294952:A:G	L1073P	0.999
13:75294990:C:A	R1060S	0.999
13:75294990:C:G	R1060S	0.999
13:75295004:A:C	Y1056D	0.999
13:75295004:A:G	Y1056H	0.999

dbSNP variants (sampled 300 via entrez): RS1000003664 (13:75314812 C>A), RS1000020294 (13:75383258 G>A,C), RS1000022455 (13:75442487 T>C), RS1000055968 (13:75383546 T>A,C), RS1000075280 (13:75339466 T>C), RS1000079652 (13:75424907 C>A,T), RS1000091176 (13:75291637 C>A,G,T), RS1000094734 (13:75483964 A>G), RS1000098297 (13:75359534 T>A,C), RS1000103636 (13:75466124 A>C), RS1000107358 (13:75352425 T>C), RS1000114044 (13:75429718 T>C,G), RS1000116463 (13:75406642 T>C), RS1000126408 (13:75445726 T>C), RS1000193939 (13:75448413 C>T)

Disease associations

OMIM: gene MIM:612465 | disease phenotypes: MIM:616087

GenCC curated gene-disease

Mondo (1): diabetes mellitus, noninsulin-dependent, 5 (MONDO:0014488)

Orphanet (0):

HPO phenotypes

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

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST000675_9	Heart failure	6.000000e-07
GCST001977_1	Diabetic retinopathy	7.000000e-06
GCST004068_34	Venous thromboembolism adjusted for sickle cell variant rs77121243-T	2.000000e-06
GCST004599_158	Mean platelet volume	6.000000e-10
GCST004601_170	Red blood cell count	1.000000e-17
GCST004602_170	Mean corpuscular volume	6.000000e-22
GCST005993_9	Mean corpuscular hemoglobin	4.000000e-08
GCST005996_40	Red blood cell count	9.000000e-09
GCST006011_40	Mean corpuscular volume	4.000000e-10
GCST007668_1	Two-hour glucose	4.000000e-17
GCST009732_1	Type 2 diabetes	1.000000e-14
GCST010396_83	Gut microbiota (bacterial taxa, hurdle binary method)	9.000000e-07
GCST90002381_587	Eosinophil count	2.000000e-09
GCST90002390_192	Mean corpuscular hemoglobin	2.000000e-45
GCST90002392_413	Mean corpuscular volume	2.000000e-61
GCST90002396_552	Mean reticulocyte volume	9.000000e-40
GCST90002403_520	Red blood cell count	5.000000e-45
GCST90011900_107	Serum alkaline phosphatase levels	6.000000e-13

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0004307	glucose tolerance test
EFO:0007874	gut microbiome measurement
EFO:0004842	eosinophil count
EFO:0010701	mean reticulocyte volume
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
sodium arsenite	decreases expression, affects cotreatment, increases abundance	3
Tretinoin	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
trichostatin A	increases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
aflatoxin B2	increases methylation	1
coumarin	affects phosphorylation	1
ciglitazone	affects binding, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	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
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Azacitidine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Cisplatin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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