TBC1D8

Summary

TBC1D8 (TBC1 domain family member 8, HGNC:17791) is a protein-coding gene on chromosome 2q11.2, encoding TBC1 domain family member 8 (O95759). May act as a GTPase-activating protein for Rab family protein(s).

Predicted to enable GTPase activator activity. Predicted to be involved in blood circulation and positive regulation of cell population proliferation. Predicted to be located in membrane.

Source: NCBI Gene 11138 — RefSeq curated summary.

At a glance

• GWAS associations: 19
• Clinical variants (ClinVar): 162 total
• MANE Select transcript: NM_001330348

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17791
Approved symbol	TBC1D8
Name	TBC1 domain family member 8
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	HBLP1, VRP, AD3, GRAMD8
Ensembl gene	ENSG00000204634
Ensembl biotype	protein_coding
Entrez	11138

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 19 protein_coding, 5 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000376840, ENST00000409318, ENST00000462819, ENST00000463469, ENST00000473937, ENST00000481317, ENST00000485851, ENST00000485875, ENST00000487392, ENST00000494011, ENST00000870702, ENST00000870703, ENST00000870704, ENST00000870705, ENST00000870706, ENST00000870707, ENST00000870708, ENST00000870709, ENST00000870710, ENST00000920764, ENST00000920765, ENST00000920766, ENST00000958228, ENST00000958229, ENST00000958230, ENST00000958231, ENST00000958232

RefSeq mRNA: 2 — MANE Select: NM_001330348 NM_001102426, NM_001330348

CCDS: CCDS46375, CCDS82486

Canonical transcript exons

ENST00000409318 — 20 exons

Exon	Start	End
ENSE00001471852	101010929	101011026
ENSE00001471862	101022281	101022521
ENSE00001471865	101027383	101027451
ENSE00001471866	101028048	101028146
ENSE00001471875	101032268	101032385
ENSE00001471879	101033544	101033758
ENSE00001471881	101036018	101036168
ENSE00001471883	101037532	101037708
ENSE00001471887	101038461	101038655
ENSE00001471890	101040178	101040385
ENSE00001506618	101011451	101011540
ENSE00001614993	101054108	101054336
ENSE00001710012	101050401	101050641
ENSE00001715074	101059421	101059539
ENSE00002113122	101151127	101151382
ENSE00003474970	101028303	101028432
ENSE00003568848	101090209	101090364
ENSE00003599747	101029491	101029776
ENSE00003606493	101021681	101021746
ENSE00003909594	101007228	101008273

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 97.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.5295 / max 550.3680, expressed in 1553 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29930	9.2319	1434
29931	1.8278	997
29933	0.4091	232
29929	0.0607	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	97.06	gold quality
bronchial epithelial cell	CL:0002328	96.83	gold quality
epithelium of bronchus	UBERON:0002031	96.70	gold quality
bronchus	UBERON:0002185	96.60	gold quality
gastrocnemius	UBERON:0001388	96.11	gold quality
seminal vesicle	UBERON:0000998	95.90	gold quality
gluteal muscle	UBERON:0002000	95.63	gold quality
muscle of leg	UBERON:0001383	95.39	gold quality
nasal cavity epithelium	UBERON:0005384	95.34	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.22	gold quality
body of pancreas	UBERON:0001150	95.19	gold quality
right uterine tube	UBERON:0001302	95.14	gold quality
muscle organ	UBERON:0001630	94.72	gold quality
right lung	UBERON:0002167	94.32	gold quality
body of stomach	UBERON:0001161	94.21	gold quality
skin of leg	UBERON:0001511	94.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.61	gold quality
nasal cavity mucosa	UBERON:0001826	93.55	gold quality
cardia of stomach	UBERON:0001162	93.45	gold quality
metanephros cortex	UBERON:0010533	93.43	gold quality
body of tongue	UBERON:0011876	93.28	gold quality
skin of abdomen	UBERON:0001416	93.24	gold quality
vastus lateralis	UBERON:0001379	93.23	gold quality
gall bladder	UBERON:0002110	93.15	gold quality
skeletal muscle tissue	UBERON:0001134	93.04	gold quality
triceps brachii	UBERON:0001509	93.03	gold quality
deltoid	UBERON:0001476	92.98	gold quality
quadriceps femoris	UBERON:0001377	92.96	gold quality
tibialis anterior	UBERON:0001385	92.94	gold quality
stomach	UBERON:0000945	92.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	135.47
E-CURD-119	yes	23.45
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• isolated a TBC Rab-GAP cellular binding partner interacting with the N terminus of HCV NS5A; depleting the expression of this partner severely impairs HCV RNA replication with no obvious effect on cell viability (PMID:17686842)
• TBC1D8 drives ovarian cancer tumorigenesis and metabolic reprogramming and serves as an independent prognosis factor for ovarian cancer patients (PMID:30809301)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	TBC1D8	ENSDARG00000104493
mus_musculus	Tbc1d8	ENSMUSG00000003134
rattus_norvegicus	Tbc1d8	ENSRNOG00000013583

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), 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), TBC1D26 (ENSG00000214946), TBC1D3G (ENSG00000260287), TBC1D3K (ENSG00000273513), TBC1D3H (ENSG00000274226), TBC1D3D (ENSG00000274419), TBC1D3L (ENSG00000274512), TBC1D3 (ENSG00000274611)

Protein

Protein identifiers

TBC1 domain family member 8 — O95759 (reviewed: O95759)

Alternative names: AD 3, Vascular Rab-GAP/TBC-containing protein

All UniProt accessions (2): O95759, J3KQ40

UniProt curated annotations — full annotation on UniProt →

Function. May act as a GTPase-activating protein for Rab family protein(s).

Domain organisation. The arginine and glutamine fingers are critical for the GTPase-activating mechanism, they pull out Rab’s ‘switch 2’ glutamine and insert in Rab’s active site.

Isoforms (2)

UniProt ID	Names	Canonical?
O95759-1	1	yes
O95759-2	2

RefSeq proteins (2): NP_001095896, NP_001317277* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000195	Rab-GAP-TBC_dom	Domain
IPR004182	GRAM	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR035969	Rab-GAP_TBC_sf	Homologous_superfamily
IPR036009	TBC1D8_PH-GRAM1	Domain
IPR036016	TBC1D8_PH-GRAM2	Domain

Pfam: PF00566, PF02893

UniProt features (16 total): sequence variant 5, domain 3, sequence conflict 2, site 2, chain 1, region of interest 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95759-F1	79.20	0.43

Functional residue map

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

Catalytic / active sites (2): 552 (arginine finger); 591 (glutamine finger)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 251 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_CIRCULATORY_SYSTEM_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, DITTMER_PTHLH_TARGETS_UP, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, YAGUE_PRETUMOR_DRUG_RESISTANCE_UP, GOBP_CILIUM_ORGANIZATION, GOBP_ORGANELLE_ASSEMBLY, TGACATY_UNKNOWN

GO Biological Process (3): blood circulation (GO:0008015), positive regulation of cell population proliferation (GO:0008284), system process (GO:0003008)

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

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
circulatory system process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
multicellular organismal process	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

718 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBC1D8	TBC1D21	Q8IYX1	530
TBC1D8	TBC1D22B	Q9NU19	516
TBC1D8	TBC1D13	Q9NVG8	506
TBC1D8	CDC16	Q13042	493
TBC1D8	TBC1D17	Q9HA65	487
TBC1D8	TBC1D16	Q8TBP0	476
TBC1D8	TBC1D22A	Q8WUA7	464
TBC1D8	TBC1D20	Q96BZ9	461
TBC1D8	RPL31	P12947	435
TBC1D8	TBC1D15	Q8TC07	411
TBC1D8	RNF149	Q8NC42	409
TBC1D8	DIPK1C	Q0P6D2	408
TBC1D8	TBC1D19	Q8N5T2	402
TBC1D8	SSBP2	P81877	400
TBC1D8	TBC1D24	Q9ULP9	396

IntAct

21 interactions, top by confidence:

A	B	Type	Score
TBC1D8	TRAF1	psi-mi:“MI:0915”(physical association)	0.560
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
SCRIB	TBC1D8	psi-mi:“MI:0407”(direct interaction)	0.440
THOC2		psi-mi:“MI:0914”(association)	0.350
MRPL50	MRPL43	psi-mi:“MI:0914”(association)	0.350
	BTAF1	psi-mi:“MI:0914”(association)	0.350
TACSTD2	RIMOC1	psi-mi:“MI:0914”(association)	0.350
TBC1D8	ENPP1	psi-mi:“MI:0914”(association)	0.350
COMTD1	TARS3	psi-mi:“MI:0914”(association)	0.350
GPR45	VWA8	psi-mi:“MI:0914”(association)	0.350
GZMH	DENND11	psi-mi:“MI:0914”(association)	0.350
ADAM7	RIOK3	psi-mi:“MI:0914”(association)	0.350
BTNL9	TNPO2	psi-mi:“MI:0914”(association)	0.350
EPHA1	ENC1	psi-mi:“MI:0914”(association)	0.350
RIC3	QSOX1	psi-mi:“MI:0914”(association)	0.350
S1PR3	STXBP3	psi-mi:“MI:0914”(association)	0.350
gE	TBC1D8	psi-mi:“MI:0914”(association)	0.350
TBC1D8	TRAF1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (56): TBC1D8 (Synthetic Growth Defect), TBC1D8 (Affinity Capture-MS), TBC1D8 (Affinity Capture-MS), TBC1D8 (Two-hybrid), TBC1D8 (Affinity Capture-MS), TBC1D8 (Proximity Label-MS), TBC1D8 (Proximity Label-MS), TBC1D8 (Proximity Label-MS), TBC1D8 (Proximity Label-MS), TBC1D8 (Proximity Label-MS), TBC1D8 (Proximity Label-MS), TBC1D8 (Proximity Label-MS), TBC1D8 (Proximity Label-MS), TBC1D8 (Proximity Label-MS), TBC1D8 (Proximity Label-MS)

ESM2 similar proteins: A1Z7T0, A1ZBD6, A3KGB4, A6QQP7, B0R0W9, B3DLH6, C7J8E5, G5EDB9, G5EF60, G5EGS5, H2KZZ6, O75923, O88763, O95759, P24583, P34609, P36582, P49846, P87141, Q0IIM8, Q0IQN5, Q14644, Q18685, Q2WGJ9, Q4FZZ1, Q5D891, Q5RJH2, Q60790, Q69ZN7, Q6AZN6, Q6DN12, Q6PF93, Q7Z7A4, Q8MLZ5, Q8NEB9, Q8VHQ7, Q93YQ1, Q96C24, Q9ESD7, Q9FJG3

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	135
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

4955 predictions. Top by Δscore:

Variant	Effect	Δscore
2:101006072:G:GG	donor_gain	1.0000
2:101008270:CTCT:C	acceptor_gain	1.0000
2:101008274:C:CC	acceptor_gain	1.0000
2:101011028:T:C	acceptor_gain	1.0000
2:101011542:T:C	acceptor_gain	1.0000
2:101027378:CGTA:C	donor_loss	1.0000
2:101027379:GTA:G	donor_loss	1.0000
2:101027380:TA:T	donor_loss	1.0000
2:101027381:ACCTT:A	donor_loss	1.0000
2:101027382:C:CT	donor_loss	1.0000
2:101027452:C:CC	acceptor_gain	1.0000
2:101027453:T:C	acceptor_gain	1.0000
2:101027453:T:TC	acceptor_gain	1.0000
2:101028047:CCA:C	donor_gain	1.0000
2:101028142:AATTT:A	acceptor_gain	1.0000
2:101028143:ATTT:A	acceptor_gain	1.0000
2:101028144:TTT:T	acceptor_gain	1.0000
2:101028145:TT:T	acceptor_gain	1.0000
2:101028145:TTCTG:T	acceptor_loss	1.0000
2:101028146:TC:T	acceptor_loss	1.0000
2:101028147:C:CC	acceptor_gain	1.0000
2:101028147:CTGCA:C	acceptor_loss	1.0000
2:101029485:GCCCA:G	donor_loss	1.0000
2:101029486:CCCA:C	donor_loss	1.0000
2:101029487:CCA:C	donor_loss	1.0000
2:101029488:CA:C	donor_loss	1.0000
2:101029489:A:T	donor_loss	1.0000
2:101029490:C:CG	donor_loss	1.0000
2:101029521:T:TA	donor_gain	1.0000
2:101029772:TGCCC:T	acceptor_gain	1.0000

AlphaMissense

7670 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:101090304:C:G	R63P	1.000
2:101050624:A:G	W202R	0.999
2:101050624:A:T	W202R	0.999
2:101054151:G:C	S181R	0.999
2:101054151:G:T	S181R	0.999
2:101054153:T:G	S181R	0.999
2:101059437:A:T	V114D	0.999
2:101059500:A:G	L93P	0.999
2:101090298:A:G	L65P	0.999
2:101151177:A:G	F26S	0.999
2:101151205:A:G	W17R	0.999
2:101151205:A:T	W17R	0.999
2:101151250:A:G	W2R	0.999
2:101151250:A:T	W2R	0.999
2:101036033:A:G	W515R	0.998
2:101036033:A:T	W515R	0.998
2:101054168:C:G	G176R	0.998
2:101059439:A:C	F113L	0.998
2:101059439:A:T	F113L	0.998
2:101059440:A:G	F113S	0.998
2:101059441:A:G	F113L	0.998
2:101090259:G:T	A78E	0.998
2:101090301:A:G	I64T	0.998
2:101090301:A:T	I64N	0.998
2:101151163:G:T	R31S	0.998
2:101151171:A:G	L28P	0.998
2:101151203:C:A	W17C	0.998
2:101151203:C:G	W17C	0.998
2:101151248:C:A	W2C	0.998
2:101151248:C:G	W2C	0.998

dbSNP variants (sampled 300 via entrez): RS1000007869 (2:101077477 C>G), RS1000023275 (2:101091581 T>A), RS1000050592 (2:101034313 T>G), RS1000057499 (2:101132359 A>C,G,T), RS1000080641 (2:101056249 G>A), RS1000113512 (2:101029066 A>C), RS1000184493 (2:101041743 G>A), RS1000194885 (2:101126754 G>A), RS1000231025 (2:101134298 G>A), RS1000237724 (2:101134621 T>C), RS1000247288 (2:101126424 G>A), RS1000288647 (2:101043668 G>A), RS1000395132 (2:101011366 C>T), RS1000405701 (2:101017268 T>C), RS1000425853 (2:101079810 A>C,G,T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000698_2	Osteoporosis-related phenotypes	1.000000e-07
GCST003075_86	Cognitive decline rate in late mild cognitive impairment	6.000000e-07
GCST004613_92	Sum neutrophil eosinophil counts	6.000000e-09
GCST004614_129	Granulocyte count	3.000000e-09
GCST004626_17	Myeloid white cell count	1.000000e-09
GCST006412_25	Intraocular pressure	2.000000e-09
GCST006632_2	Decline in glucose metabolism in posterior cingulate cortex	1.000000e-06
GCST010151_4	Carotid intima media thickness x smoking interaction	6.000000e-09
GCST012489_74	Heel bone mineral density x serum urate levels interaction	4.000000e-09
GCST90002385_138	High light scatter reticulocyte count	1.000000e-10
GCST90002386_254	High light scatter reticulocyte percentage of red cells	4.000000e-10
GCST90002389_117	Lymphocyte percentage of white cells	5.000000e-14
GCST90002398_342	Neutrophil count	2.000000e-24
GCST90002399_149	Neutrophil percentage of white cells	1.000000e-15
GCST90002405_133	Reticulocyte count	8.000000e-12
GCST90002406_51	Reticulocyte fraction of red cells	5.000000e-11
GCST90002407_55	White blood cell count	4.000000e-14
GCST90013663_9	Alanine aminotransferase levels	4.000000e-10
GCST90013664_35	Aspartate aminotransferase levels	1.000000e-08

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0004695	intraocular pressure measurement
EFO:0009392	glucose metabolism decline measurement
EFO:0006527	smoking status measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0007986	reticulocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression	5
Tobacco Smoke Pollution	affects expression, decreases expression	3
sodium arsenite	affects methylation, decreases expression	2
Acetaminophen	increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Estradiol	affects cotreatment, decreases expression, decreases reaction	2
Tetrachlorodibenzodioxin	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	2
methylmercuric chloride	decreases expression	1
trichostatin A	decreases expression	1
cupric chloride	decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	decreases expression	1
monomethylarsonous acid	decreases expression	1
K 7174	increases expression	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
Zoledronic Acid	increases expression	1
Panobinostat	decreases expression	1
Caffeine	increases phosphorylation	1
Calcitriol	increases expression, affects cotreatment	1
Cisplatin	affects cotreatment, increases expression	1
Curcumin	increases expression	1
Hydrogen Peroxide	affects expression	1
Mitoxantrone	affects response to substance	1
Quercetin	increases expression	1
Dihydrotestosterone	increases expression	1

Clinical trials (associated diseases)

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