ARHGAP25

Summary

ARHGAP25 (Rho GTPase activating protein 25, HGNC:28951) is a protein-coding gene on chromosome 2p13.3, encoding Rho GTPase-activating protein 25 (P42331). GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.

ARHGAPs, such as ARHGAP25, encode negative regulators of Rho GTPases (see ARHA; MIM 165390), which are implicated in actin remodeling, cell polarity, and cell migration (Katoh and Katoh, 2004 [PubMed 15254788]).

Source: NCBI Gene 9938 — RefSeq curated summary.

At a glance

• GWAS associations: 19
• Clinical variants (ClinVar): 105 total
• MANE Select transcript: NM_001007231

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28951
Approved symbol	ARHGAP25
Name	Rho GTPase activating protein 25
Location	2p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0053
Ensembl gene	ENSG00000163219
Ensembl biotype	protein_coding
OMIM	610587
Entrez	9938

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 8 protein_coding_CDS_not_defined, 7 protein_coding, 2 nonsense_mediated_decay

ENST00000409030, ENST00000409202, ENST00000409220, ENST00000456116, ENST00000463061, ENST00000463483, ENST00000467265, ENST00000473986, ENST00000479844, ENST00000481684, ENST00000485573, ENST00000485700, ENST00000488795, ENST00000491237, ENST00000496266, ENST00000497079, ENST00000497259

RefSeq mRNA: 7 — MANE Select: NM_001007231 NM_001007231, NM_001166276, NM_001166277, NM_001364819, NM_001364820, NM_001364821, NM_014882

CCDS: CCDS33214, CCDS46312, CCDS54363, CCDS54364

Canonical transcript exons

ENST00000409202 — 11 exons

Exon	Start	End
ENSE00001072548	68819123	68819319
ENSE00001072551	68822340	68822872
ENSE00001577730	68825987	68826833
ENSE00001887114	68734811	68735260
ENSE00003547196	68775221	68775420
ENSE00003548564	68817873	68817994
ENSE00003694439	68816289	68816362
ENSE00003971811	68787840	68787956
ENSE00003971812	68782233	68782320
ENSE00003971813	68807273	68807480
ENSE00003971814	68813287	68813419

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 97.70.

FANTOM5 (CAGE): breadth broad, TPM avg 18.3145 / max 1323.8581, expressed in 726 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20721	4.2732	461
20720	3.6292	478
20711	3.2734	358
20710	1.7470	316
20712	1.4527	374
20715	1.3462	319
20719	0.5286	121
20714	0.4881	240
20723	0.3461	108
20718	0.3262	113

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.70	gold quality
blood	UBERON:0000178	97.38	gold quality
spleen	UBERON:0002106	95.50	gold quality
lymph node	UBERON:0000029	94.87	gold quality
leukocyte	CL:0000738	93.68	gold quality
monocyte	CL:0000576	93.32	gold quality
bone marrow cell	CL:0002092	93.28	gold quality
mononuclear cell	CL:0000842	93.24	gold quality
vermiform appendix	UBERON:0001154	92.48	gold quality
bone marrow	UBERON:0002371	90.86	gold quality
periodontal ligament	UBERON:0008266	88.87	gold quality
caecum	UBERON:0001153	88.35	gold quality
tonsil	UBERON:0002372	86.63	gold quality
colonic epithelium	UBERON:0000397	86.61	gold quality
trabecular bone tissue	UBERON:0002483	86.11	gold quality
upper lobe of left lung	UBERON:0008952	85.52	gold quality
upper lobe of lung	UBERON:0008948	84.70	gold quality
gall bladder	UBERON:0002110	84.29	gold quality
right lung	UBERON:0002167	83.90	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.79	gold quality
epithelium of nasopharynx	UBERON:0001951	81.99	gold quality
omental fat pad	UBERON:0010414	81.65	gold quality
peritoneum	UBERON:0002358	81.60	gold quality
lung	UBERON:0002048	81.50	gold quality
rectum	UBERON:0001052	81.37	gold quality
adipose tissue of abdominal region	UBERON:0007808	81.21	gold quality
small intestine	UBERON:0002108	80.90	gold quality
left ovary	UBERON:0002119	80.56	gold quality
apex of heart	UBERON:0002098	79.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.25	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-11011	yes	1285.08
E-CURD-122	yes	21.23
E-ANND-3	yes	12.14
E-GEOD-130148	yes	7.26
E-CURD-119	yes	4.32
E-MTAB-6075	no	582.64
E-MTAB-6386	no	433.71
E-CURD-112	no	3.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting ARHGAP25, 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-4531	99.99	69.70	3181
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-653-3P	98.31	67.71	1542
HSA-MIR-5585-3P	98.25	67.41	941
HSA-MIR-4786-5P	97.45	67.89	924
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299

Literature-anchored findings (GeneRIF, showing 5)

• ARHGAP25 negatively regulates the metastatic potential of CRC cells via the Wnt/beta-catenin pathway (PMID:31228451)
• ARHGAP25 Inhibits Pancreatic Adenocarcinoma Growth by Suppressing Glycolysis via AKT/mTOR Pathway. (PMID:33994864)
• A novel BRET-Based GAP assay reveals phosphorylation-dependent regulation of the RAC-specific GTPase activating protein ARHGAP25. (PMID:36190314)
• Relationship between the expression of ARHGAP25 and RhoA in non-small cell lung cancer and vasculogenic mimicry. (PMID:36207695)
• ARHGAP25 suppresses the development of breast cancer by an ARHGAP25/Wnt/ASCL2 feedback loop. (PMID:37326327)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgap25	ENSDARG00000061784
mus_musculus	Arhgap25	ENSMUSG00000030047
rattus_norvegicus	Arhgap25	ENSRNOG00000009347

Paralogs (2): ARHGAP22 (ENSG00000128805), ARHGAP24 (ENSG00000138639)

Protein

Protein identifiers

Rho GTPase-activating protein 25 — P42331 (reviewed: P42331)

Alternative names: Rho-type GTPase-activating protein 25

All UniProt accessions (6): C9JB56, P42331, F8WAV9, F8WDF6, H7C4P1, V9HWC8

UniProt curated annotations — full annotation on UniProt →

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

Isoforms (6)

UniProt ID	Names	Canonical?
P42331-1	1	yes
P42331-2	2
P42331-3	3
P42331-4	4
P42331-5	5
P42331-6	6

RefSeq proteins (7): NP_001007232, NP_001159748, NP_001159749, NP_001351748, NP_001351749, NP_001351750, NP_055697 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR001849	PH_domain	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR051025	RhoGAP	Family

Pfam: PF00169, PF00620

UniProt features (30 total): strand 8, modified residue 4, splice variant 4, sequence variant 3, compositionally biased region 3, domain 2, region of interest 2, chain 1, helix 1, coiled-coil region 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1V89	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42331-F1	70.41	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 (1): 199 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (4): 362, 395, 406, 536

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9013149	RAC1 GTPase cycle

MSigDB gene sets: 227 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, MODULE_45, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, ONDER_CDH1_TARGETS_3_DN, GOBP_NEGATIVE_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, BILD_HRAS_ONCOGENIC_SIGNATURE, SMITH_TERT_TARGETS_DN, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GNF2_ICAM3, GOBP_ACTIN_FILAMENT_ORGANIZATION, MODULE_301, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, DORSEY_GAB2_TARGETS

GO Biological Process (5): phagocytosis, engulfment (GO:0006911), actin filament organization (GO:0007015), signal transduction (GO:0007165), negative regulation of small GTPase mediated signal transduction (GO:0051058), regulation of small GTPase mediated signal transduction (GO:0051056)

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

GO Cellular Component (1): phagocytic cup (GO:0001891)

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
small GTPase-mediated signal transduction	2
phagocytosis	1
plasma membrane invagination	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of small GTPase mediated signal transduction	1
negative regulation of intracellular signal transduction	1
regulation of intracellular signal transduction	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
binding	1
plasma membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1096 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGAP25	STK32A	Q8WU08	449
ARHGAP25	DMRTB1	Q96MA1	424
ARHGAP25	PLD5	Q8N7P1	396
ARHGAP25	MTRF1L	Q9UGC7	385
ARHGAP25	TRPC4AP	Q8TEL6	371
ARHGAP25	ATG7	O95352	367
ARHGAP25	DPYSL3	Q14195	356
ARHGAP25	NHLRC2	Q8NBF2	354
ARHGAP25	FAM163B	P0C2L3	352
ARHGAP25	EVI2B	P34910	347
ARHGAP25	GPR88	Q9GZN0	345
ARHGAP25	GSPT1	P15170	337
ARHGAP25	HINFP	Q9BQA5	336
ARHGAP25	CDC42	P21181	327
ARHGAP25	ARHGAP1	Q07960	320

IntAct

6 interactions, top by confidence:

A	B	Type	Score
Tax	TAX1BP3	psi-mi:“MI:0914”(association)	0.520
	ARHGAP25	psi-mi:“MI:0915”(physical association)	0.370
ARHGAP25	HTT	psi-mi:“MI:0915”(physical association)	0.370
HTT	ARHGAP25	psi-mi:“MI:0915”(physical association)	0.370
ARHGAP25	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (75): DMWD (Affinity Capture-MS), DYNC2H1 (Affinity Capture-MS), DSTYK (Affinity Capture-MS), GTF2H2 (Affinity Capture-MS), POLD1 (Affinity Capture-MS), SEC23IP (Affinity Capture-MS), DPYSL4 (Affinity Capture-MS), ACACA (Affinity Capture-MS), TBL3 (Affinity Capture-MS), CAMK2D (Affinity Capture-MS), CAMK2G (Affinity Capture-MS), UBA6 (Affinity Capture-MS), DDX11L8 (Affinity Capture-MS), MSTO1 (Affinity Capture-MS), ATG7 (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: A0A0G2JTR4, A2AB59, A2RUV4, A4IF90, A4II46, A6QNS3, A6X8Z5, A7E300, A7KAX9, A8WRJ2, B2RTY4, D3ZZN9, E7EZG2, E7F3F0, F1LXF1, O14559, O43182, O54834, O74360, O94988, P11274, P15882, P30337, P34288, P42331, P46941, P52757, P98171, Q03070, Q08DP6, Q10164, Q12979, Q13459, Q15311, Q17QN0, Q20498, Q2M1Z3, Q3UIA2, Q53QZ3, Q54FG5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	6
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2218 predictions. Top by Δscore:

Variant	Effect	Δscore
2:68782295:G:T	donor_gain	1.0000
2:68807272:GCAGT:G	acceptor_gain	1.0000
2:68807429:TG:T	donor_gain	1.0000
2:68807437:C:G	donor_gain	1.0000
2:68807477:ACAG:A	donor_loss	1.0000
2:68807478:CAGG:C	donor_loss	1.0000
2:68807479:AGGT:A	donor_loss	1.0000
2:68807480:GGTAC:G	donor_loss	1.0000
2:68807481:GT:G	donor_loss	1.0000
2:68807482:T:A	donor_loss	1.0000
2:68819118:TTCA:T	acceptor_loss	1.0000
2:68819121:A:AG	acceptor_gain	1.0000
2:68819121:A:G	acceptor_loss	1.0000
2:68819121:AG:A	acceptor_gain	1.0000
2:68819121:AGG:A	acceptor_gain	1.0000
2:68819122:G:GA	acceptor_gain	1.0000
2:68819122:GG:G	acceptor_gain	1.0000
2:68819122:GGG:G	acceptor_gain	1.0000
2:68819122:GGGA:G	acceptor_gain	1.0000
2:68819122:GGGAC:G	acceptor_gain	1.0000
2:68819315:GCATG:G	donor_gain	1.0000
2:68819316:CATG:C	donor_loss	1.0000
2:68819317:ATGG:A	donor_loss	1.0000
2:68819318:TGGTA:T	donor_loss	1.0000
2:68819320:G:GG	donor_gain	1.0000
2:68819321:T:G	donor_loss	1.0000
2:68822339:GACAA:G	acceptor_gain	1.0000
2:68822829:G:GT	donor_gain	1.0000
2:68822871:AA:A	donor_gain	1.0000
2:68822872:AGT:A	donor_loss	1.0000

AlphaMissense

4305 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000019210 (2:68816926 A>G), RS1000033131 (2:68818520 G>T), RS1000054264 (2:68777296 G>A), RS1000070232 (2:68725642 A>G), RS1000071131 (2:68734589 G>A), RS1000075353 (2:68790548 A>G), RS1000085139 (2:68818838 T>C), RS1000089774 (2:68771584 G>A), RS1000095067 (2:68714944 C>G), RS1000110713 (2:68708889 T>C), RS1000121154 (2:68771250 C>T), RS1000122372 (2:68804664 A>C,G), RS1000173491 (2:68774798 A>C,G), RS1000266495 (2:68802476 T>A), RS1000273209 (2:68821096 T>C)

Disease associations

OMIM: gene MIM:610587 | 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
GCST004603_209	Platelet count	5.000000e-12
GCST004607_217	Plateletcrit	5.000000e-21
GCST005348_70	Total body bone mineral density	2.000000e-08
GCST005559_12	Virologic severity in Herpes simplex virus type 2 infection	1.000000e-06
GCST005796_4	Lumbar spine bone mineral density	4.000000e-08
GCST006585_2711	Blood protein levels	9.000000e-06
GCST006979_10	Heel bone mineral density	2.000000e-11
GCST011754_1	Nicotine dependence	4.000000e-08
GCST012490_558	Femur bone mineral density x serum urate levels interaction	9.000000e-12
GCST90002389_115	Lymphocyte percentage of white cells	1.000000e-15
GCST90002393_192	Monocyte count	1.000000e-19
GCST90002394_122	Monocyte percentage of white cells	4.000000e-15
GCST90002398_339	Neutrophil count	2.000000e-09
GCST90002399_146	Neutrophil percentage of white cells	2.000000e-12
GCST90002400_318	Plateletcrit	3.000000e-31
GCST90002402_238	Platelet count	5.000000e-16
GCST90002406_20	Reticulocyte fraction of red cells	4.000000e-09
GCST90011900_3	Serum alkaline phosphatase levels	7.000000e-09
GCST90013406_157	Liver enzyme levels (alkaline phosphatase)	4.000000e-15

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0009010	HSV2 virologic severity measurement
EFO:0007701	spine bone mineral density
EFO:0009270	heel bone mineral density
EFO:0004531	urate measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0007990	neutrophil percentage of leukocytes
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

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	decreases expression, increases expression	3
Silicon Dioxide	decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
sodium arsenate	increases abundance, increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Air Pollutants	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	increases abundance, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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