ARHGAP8

Summary

ARHGAP8 (Rho GTPase activating protein 8, HGNC:677) is a protein-coding gene on chromosome 22q13.31, encoding Rho GTPase-activating protein 8 (P85298). GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.

This gene encodes a member of the RHOGAP family. GAP (GTPase-activating) family proteins participate in signaling pathways that regulate cell processes involved in cytoskeletal changes. GAP proteins alternate between an active (GTP-bound) and inactive (GDP-bound) state based on the GTP:GDP ratio in the cell. This family member is a multidomain protein that functions to promote Erk activation and cell motility. Alternative splicing results in multiple transcript variants. Read-through transcripts from the upstream proline rich 5, renal (PRR5) gene into this gene also exist, which led to the original description of PRR5 and ARHGAP8 being a single gene.

Source: NCBI Gene 23779 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 111 total — 2 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_181335

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:677
Approved symbol	ARHGAP8
Name	Rho GTPase activating protein 8
Location	22q13.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20185, BPGAP1
Ensembl gene	ENSG00000241484
Ensembl biotype	protein_coding
OMIM	609405
Entrez	23779

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 32 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000336963, ENST00000356099, ENST00000389772, ENST00000389774, ENST00000396119, ENST00000412433, ENST00000447333, ENST00000460809, ENST00000469342, ENST00000469872, ENST00000495219, ENST00000498310, ENST00000859071, ENST00000859072, ENST00000859073, ENST00000859074, ENST00000859075, ENST00000859076, ENST00000859077, ENST00000859078, ENST00000859079, ENST00000859080, ENST00000859081, ENST00000859082, ENST00000859083, ENST00000929956, ENST00000929958, ENST00000929959, ENST00000929960, ENST00000929961, ENST00000929962, ENST00000929963, ENST00000929964, ENST00000954603, ENST00000954604, ENST00000954605, ENST00000954606, ENST00000954607, ENST00000954608

RefSeq mRNA: 3 — MANE Select: NM_181335 NM_001017526, NM_001198726, NM_181335

CCDS: CCDS14060, CCDS33664, CCDS56233

Canonical transcript exons

ENST00000356099 — 12 exons

Exon	Start	End
ENSE00002094227	44752575	44752627
ENSE00003477616	44862275	44862784
ENSE00003485566	44847973	44848050
ENSE00003497355	44825483	44825593
ENSE00003505387	44848932	44849060
ENSE00003505428	44822371	44822469
ENSE00003523479	44808307	44808438
ENSE00003594661	44845269	44845342
ENSE00003601848	44814672	44814758
ENSE00003612018	44802077	44802164
ENSE00003685792	44786457	44786606
ENSE00003694539	44859731	44859834

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 98.17.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9773 / max 78.5176, expressed in 494 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192692	2.8792	494
192693	0.0982	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.17	gold quality
metanephros cortex	UBERON:0010533	95.04	gold quality
left lobe of thyroid gland	UBERON:0001120	94.42	gold quality
right lobe of thyroid gland	UBERON:0001119	94.40	gold quality
mucosa of transverse colon	UBERON:0004991	93.76	gold quality
thyroid gland	UBERON:0002046	92.70	gold quality
lower esophagus mucosa	UBERON:0035834	92.51	gold quality
body of pancreas	UBERON:0001150	90.23	gold quality
minor salivary gland	UBERON:0001830	88.64	gold quality
adenohypophysis	UBERON:0002196	88.03	gold quality
spleen	UBERON:0002106	87.78	gold quality
saliva-secreting gland	UBERON:0001044	86.83	gold quality
rectum	UBERON:0001052	86.42	gold quality
adult mammalian kidney	UBERON:0000082	85.90	gold quality
transverse colon	UBERON:0001157	85.40	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.40	gold quality
pituitary gland	UBERON:0000007	84.63	gold quality
mouth mucosa	UBERON:0003729	84.48	gold quality
right lung	UBERON:0002167	83.88	gold quality
esophagus mucosa	UBERON:0002469	83.85	gold quality
cortex of kidney	UBERON:0001225	83.09	gold quality
pancreas	UBERON:0001264	82.92	gold quality
tibial nerve	UBERON:0001323	82.84	gold quality
upper lobe of left lung	UBERON:0008952	82.81	gold quality
prostate gland	UBERON:0002367	82.24	gold quality
body of stomach	UBERON:0001161	81.80	gold quality
gall bladder	UBERON:0002110	80.98	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.91	gold quality
upper lobe of lung	UBERON:0008948	80.72	gold quality
colonic epithelium	UBERON:0000397	80.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	84.86
E-HCAD-10	yes	18.87
E-ANND-3	yes	4.87
E-GEOD-81383	no	305.42

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): OLIG2

Literature-anchored findings (GeneRIF, showing 10)

• This paper compares the protein sequences and genomic structures of human and mouse ARHGAP8. (PMID:12559566)
• BPGAP1 has a role in regulating cell dynamics with BNIP-2 and Cdc42GAP homology/Sec14p-like, proline-rich, and GTPase-activating protein domains of BPGAP1 (PMID:12944407)
• RhoGAP functionally interacts with cortactin and represents a novel determinant in the regulation of cell dynamics. (PMID:15064355)
• ARHGAP8 expression was up-regulated in the majority of primary colorectal tumors analyzed in this work. (PMID:15225876)
• BPGAP1 is a novel RhoGAP that co-ordinately regulates pseudopodia and cell migration through the interplay of its BNIP-2 and Cdc42GAP homology domains. (PMID:15506981)
• findings reveal a concomitant activation of endocytosis and ERK signaling by BPGAP1 via the coupling of its proline-rich region, which targets EEN and its functional GAP domain (PMID:15944398)
• Pin1 regulates BPGAP1 function in Rho and Erk signalling, with active Mek2 serving as a novel regulatory scaffold that promotes crosstalk between RhoGAP, Pin1 and Erk in the regulation of cell migration. (PMID:20179103)
• BPGAP1 provides a crucial spatiotemporal checkpoint where JNK and MP1/MEK1 work in concert to regulate endosomal and nuclear ERK signaling in cell proliferation control. (PMID:28092672)
• Fusion protein PRR5-ARHGAP8 plays a role in bipolar disorder with binge eating behavior. (PMID:29391396)
• The scaffold RhoGAP protein ARHGAP8/BPGAP1 synchronizes Rac and Rho signaling to facilitate cell migration. (PMID:36598812)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Arhgap8	ENSMUSG00000078954
rattus_norvegicus	Arhgap8	ENSRNOG00000033570

Paralogs (1): ARHGAP1 (ENSG00000175220)

Protein

Protein identifiers

Rho GTPase-activating protein 8 — P85298 (reviewed: P85298)

Alternative names: Rho-type GTPase-activating protein 8

All UniProt accessions (5): B1AHC2, B1AHF8, P85298, F8W6F4, F8WCV8

UniProt curated annotations — full annotation on UniProt →

Function. GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.

Tissue specificity. Highly expressed in kidney and placenta. Also expressed in colon, skeletal muscle, small intestine, stomach, and testis. Not detected in brain, liver or spleen. Overexpressed in the majority of colorectal tumors examined.

Isoforms (5)

UniProt ID	Names	Canonical?
P85298-1	1	yes
P85298-2	2
P85298-3	3
P85298-4	4
P85298-5	5

RefSeq proteins (3): NP_001017526, NP_001185655, NP_851852* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR001251	CRAL-TRIO_dom	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR036865	CRAL-TRIO_dom_sf	Homologous_superfamily

Pfam: PF00620, PF13716

UniProt features (15 total): splice variant 6, sequence variant 4, domain 2, chain 1, region of interest 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P85298-F1	76.51	0.35

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 (1): 263 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8980692	RHOA GTPase cycle

MSigDB gene sets: 104 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, AP1_01, GCANCTGNY_MYOD_Q6, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, RACCACAR_AML_Q6, GOBP_VESICLE_MEDIATED_TRANSPORT, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, EVI1_05, NFKB_C, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, FOSTER_TOLERANT_MACROPHAGE_DN, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION

GO Biological Process (5): small GTPase-mediated signal transduction (GO:0007264), regulation of small GTPase mediated signal transduction (GO:0051056), positive regulation of ERK1 and ERK2 cascade (GO:0070374), negative regulation of endocytic recycling (GO:2001136), signal transduction (GO:0007165)

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

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
intracellular signaling cassette	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
negative regulation of intracellular transport	1
endocytic recycling	1
regulation of endocytic recycling	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

444 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGAP8	PRR5	P85299	914
ARHGAP8	CDC42	P21181	740
ARHGAP8	CTTN	Q14247	686
ARHGAP8	RHOA	P06749	551
ARHGAP8	PRR5L	Q6MZQ0	550
ARHGAP8	M0R1W7	M0R1W7	506
ARHGAP8	A6NDT3	A6NDT3	396
ARHGAP8	MAPKAP1	Q9BPZ7	383
ARHGAP8	BNIP2	Q12982	379
ARHGAP8	GART	P22102	352
ARHGAP8	ALOX5	P09917	344
ARHGAP8	PHOSPHO2	Q8TCD6	321
ARHGAP8	ITSN2	Q9NZM3	319
ARHGAP8	RICTOR	Q6R327	315
ARHGAP8	FKBP1C	Q5VVH2	311

IntAct

16 interactions, top by confidence:

A	B	Type	Score
ISOC1	ARHGAP8	psi-mi:“MI:0915”(physical association)	0.400
CFTR	ARHGAP8	psi-mi:“MI:0915”(physical association)	0.370
	AGPS	psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350
NOXO1	SOD1	psi-mi:“MI:0914”(association)	0.350
CALML3	MYO1C	psi-mi:“MI:0914”(association)	0.350
FEM1A	RNF113A	psi-mi:“MI:0914”(association)	0.350
NOXO1	HSPA8	psi-mi:“MI:0914”(association)	0.350
RBM43	MAPKAPK2	psi-mi:“MI:0914”(association)	0.350
PRR5-ARHGAP8	ARHGAP8	psi-mi:“MI:0914”(association)	0.350
FEM1A	DHRS3	psi-mi:“MI:0914”(association)	0.350
CALM1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
SLC49A4	AP3B1	psi-mi:“MI:0914”(association)	0.350

BioGRID (38): PRR5-ARHGAP8 (Affinity Capture-MS), SH3GL3 (Affinity Capture-MS), SH3GL2 (Affinity Capture-MS), SH3GL1 (Affinity Capture-MS), HTR3C (Affinity Capture-MS), PRR5-ARHGAP8 (Affinity Capture-MS), SH3GL3 (Affinity Capture-MS), SH3GL2 (Affinity Capture-MS), SH3GL1 (Affinity Capture-MS), HTR3C (Affinity Capture-MS), ARHGAP8 (Affinity Capture-MS), ARHGAP8 (Affinity Capture-MS), ARHGAP8 (Affinity Capture-RNA), SH3GL1 (Affinity Capture-MS), SH3GL1 (Affinity Capture-Western)

ESM2 similar proteins: A4Q9F4, A6QLH5, D3Z7P3, D3ZVU9, E9PV86, M0R7T9, O35652, O43414, O54804, O60242, O60347, O70512, O94925, P08887, P0C7M8, P13264, P35790, P85298, Q01134, Q08DW9, Q13202, Q13505, Q2HJ53, Q2TBM7, Q3UGX3, Q4R766, Q4R7M4, Q58DH2, Q5XI70, Q62225, Q6AYT7, Q6DN14, Q80T74, Q80UW0, Q80ZF8, Q86W50, Q8C460, Q8N2K0, Q8NBA8, Q8NHH1

Diamond homologs: B2RWW0, D3ZFJ3, E7EZG2, E7F3F0, F1LQX4, P0CAX8, P55194, P85298, Q07960, Q10164, Q14CB8, Q17R89, Q3KRB8, Q3UIA2, Q54WY8, Q54XT6, Q54Y72, Q55GP8, Q5F3G0, Q5FWK3, Q5SSM3, Q6IFT4, Q6P4F7, Q6REY9, Q6Y5D8, Q6ZT62, Q80Y19, Q8BL80, Q8BRH3, Q8N103, Q99N37, Q9CXP4, Q9P2F6, Q9WVM1, Q9Y3L3, A1A4S6, A2AB59, A2RUV4, A4IF90, A6X8Z5

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ARHGAP8	“down-regulates activity”	RHOA	“gtpase-activating protein”
MAPK8	“up-regulates activity”	ARHGAP8	phosphorylation
ARHGAP8	“up-regulates activity”	LAMTOR3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	88
Likely benign	16
Benign	3

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1526739	GRCh37/hg19 22q13.2-13.31(chr22:43451316-46662660)	Pathogenic
3062442	GRCh37/hg19 22q13.31-13.33(chr22:44502872-51183871)x1	Pathogenic
3062463	GRCh37/hg19 22q13.2-13.31(chr22:43920110-46548382)x1	Likely pathogenic

SpliceAI

3367 predictions. Top by Δscore:

Variant	Effect	Δscore
22:44802160:CTGGA:C	donor_gain	1.0000
22:44802162:GGA:G	donor_gain	1.0000
22:44802162:GGAGT:G	donor_loss	1.0000
22:44802163:GA:G	donor_gain	1.0000
22:44802163:GAG:G	donor_gain	1.0000
22:44802164:AG:A	donor_loss	1.0000
22:44802164:AGTAA:A	donor_loss	1.0000
22:44802165:G:C	donor_loss	1.0000
22:44802165:G:GG	donor_gain	1.0000
22:44802166:T:A	donor_loss	1.0000
22:44808302:CCCA:C	acceptor_loss	1.0000
22:44808304:CA:C	acceptor_loss	1.0000
22:44808306:G:A	acceptor_loss	1.0000
22:44808306:G:GA	acceptor_loss	1.0000
22:44808306:GGT:G	acceptor_gain	1.0000
22:44808424:G:GT	donor_gain	1.0000
22:44808425:G:GT	donor_gain	1.0000
22:44808434:AGGAA:A	donor_gain	1.0000
22:44808435:GGAA:G	donor_gain	1.0000
22:44808435:GGAAG:G	donor_gain	1.0000
22:44808436:G:GT	donor_gain	1.0000
22:44808436:GAA:G	donor_gain	1.0000
22:44808437:AAGT:A	donor_loss	1.0000
22:44808438:AGT:A	donor_loss	1.0000
22:44808439:G:GG	donor_gain	1.0000
22:44808440:T:G	donor_loss	1.0000
22:44808462:G:T	donor_gain	1.0000
22:44814667:CTCA:C	acceptor_loss	1.0000
22:44814670:A:AG	acceptor_gain	1.0000
22:44814670:A:C	acceptor_loss	1.0000

AlphaMissense

2826 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:44825574:T:C	F224L	0.994
22:44825576:T:A	F224L	0.994
22:44825576:T:G	F224L	0.994
22:44849007:T:C	L306P	0.989
22:44808357:T:A	V73D	0.986
22:44814706:C:G	H143D	0.983
22:44849019:T:A	L310H	0.983
22:44825575:T:C	F224S	0.982
22:44847993:T:C	F262L	0.978
22:44847995:C:A	F262L	0.978
22:44847995:C:G	F262L	0.978
22:44862321:C:A	A374D	0.978
22:44848990:G:C	K300N	0.977
22:44848990:G:T	K300N	0.977
22:44849019:T:G	L310R	0.977
22:44845331:T:C	L251P	0.975
22:44847994:T:C	F262S	0.971
22:44862298:C:A	N366K	0.971
22:44862298:C:G	N366K	0.971
22:44808359:T:G	Y74D	0.970
22:44845271:T:C	L231P	0.970
22:44859815:T:C	L352P	0.970
22:44859827:T:C	L356P	0.970
22:44845301:C:G	P241R	0.969
22:44862318:T:C	L373P	0.969
22:44825575:T:G	F224C	0.968
22:44862411:T:C	L404P	0.968
22:44848998:T:C	L303P	0.966
22:44862342:T:C	L381S	0.966
22:44862304:G:A	M368I	0.965

dbSNP variants (sampled 300 via entrez): RS1000040038 (22:44800153 G>C), RS1000045915 (22:44829815 C>G), RS1000056432 (22:44759921 C>T), RS1000104123 (22:44830223 C>T), RS1000116038 (22:44828885 C>T), RS1000131781 (22:44769808 C>A,G), RS1000182920 (22:44786283 G>A), RS1000220270 (22:44774448 A>C), RS1000231199 (22:44857363 G>A), RS1000243486 (22:44838780 C>A,T), RS1000261977 (22:44779465 C>A,T), RS1000284643 (22:44764818 C>T), RS1000313552 (22:44795630 G>A), RS1000314850 (22:44779685 C>T), RS1000328528 (22:44779915 T>C)

Disease associations

OMIM: gene MIM:609405 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001503_4	Electroencephalographic traits in alcoholism	3.000000e-06
GCST005387_1	Binge eating behaviour in bipolar disorder	3.000000e-08
GCST008152_100	Weight	4.000000e-06
GCST008158_70	Body mass index	9.000000e-07
GCST008471_15	Non-alcoholic fatty liver disease activity score in non-alcoholic fatty liver disease	9.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004800	frontal theta oscillation measurement
EFO:0004338	body weight
EFO:0004340	body mass index
EFO:0008421	non-alcoholic fatty liver disease severity measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, decreases methylation, increases abundance	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
sotorasib	affects cotreatment, decreases expression	1
bisphenol A	decreases expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	affects methylation	1
cobaltous chloride	decreases expression	1
tamibarotene	increases expression	1
azoxystrobin	increases expression	1
deguelin	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
pyrimidifen	increases expression	1
thifluzamide	increases expression	1
pyrachlostrobin	increases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Antimycin A	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cisplatin	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Dronabinol	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1

Clinical trials (associated diseases)

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