ARHGAP28

Summary

ARHGAP28 (Rho GTPase activating protein 28, HGNC:25509) is a protein-coding gene on chromosome 18p11.31, encoding Rho GTPase-activating protein 28 (Q9P2N2). GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.

Predicted to enable GTPase activator activity. Predicted to be involved in negative regulation of stress fiber assembly; regulation of actin filament polymerization; and regulation of small GTPase mediated signal transduction. Located in cell junction and nucleoplasm. Implicated in allergic disease. Biomarker of meningioma.

Source: NCBI Gene 79822 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 115 total — 1 pathogenic
• MANE Select transcript: NM_001366230

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25509
Approved symbol	ARHGAP28
Name	Rho GTPase activating protein 28
Location	18p11.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1314, FLJ10312
Ensembl gene	ENSG00000088756
Ensembl biotype	protein_coding
OMIM	610592
Entrez	79822

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 13 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000262227, ENST00000314319, ENST00000383472, ENST00000419673, ENST00000531294, ENST00000532723, ENST00000532996, ENST00000577524, ENST00000579245, ENST00000579689, ENST00000579796, ENST00000581099, ENST00000583410, ENST00000584287, ENST00000584387, ENST00000933700, ENST00000933701

RefSeq mRNA: 4 — MANE Select: NM_001366230 NM_001010000, NM_001366230, NM_001366231, NM_001410873

CCDS: CCDS32785, CCDS92429, CCDS92430

Canonical transcript exons

ENST00000383472 — 18 exons

Exon	Start	End
ENSE00000565524	6896502	6896626
ENSE00000665706	6894835	6894891
ENSE00000665708	6890430	6890543
ENSE00000665710	6889888	6890085
ENSE00000665714	6873409	6873574
ENSE00000665715	6870590	6870732
ENSE00001038567	6882137	6882299
ENSE00001038578	6859808	6859897
ENSE00001038585	6887157	6887239
ENSE00001038597	6851034	6851126
ENSE00001271753	6908960	6909024
ENSE00002140531	6912060	6915716
ENSE00002726174	6729716	6729943
ENSE00003612979	6837197	6837414
ENSE00003673240	6876131	6876208
ENSE00003686494	6873684	6873775
ENSE00003787141	6868150	6868234
ENSE00003788316	6824762	6824964

Expression profiles

Bgee: expression breadth ubiquitous, 202 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.0421 / max 373.7434, expressed in 919 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169266	4.6981	789
169265	1.1572	548
169267	0.7543	332
169268	0.2310	111
169269	0.1180	71
169270	0.0834	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.11	gold quality
male germ cell	CL:0000015	96.83	gold quality
left testis	UBERON:0004533	92.05	gold quality
right testis	UBERON:0004534	91.49	gold quality
testis	UBERON:0000473	90.66	gold quality
adrenal tissue	UBERON:0018303	90.58	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.23	gold quality
parietal pleura	UBERON:0002400	85.63	gold quality
colonic epithelium	UBERON:0000397	82.52	gold quality
pleura	UBERON:0000977	82.04	gold quality
placenta	UBERON:0001987	81.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.22	gold quality
right lung	UBERON:0002167	78.74	gold quality
adult organism	UBERON:0007023	78.29	gold quality
visceral pleura	UBERON:0002401	77.28	gold quality
gall bladder	UBERON:0002110	77.18	gold quality
ectocervix	UBERON:0012249	76.03	gold quality
ovary	UBERON:0000992	75.66	gold quality
corpus epididymis	UBERON:0004359	75.49	gold quality
left ovary	UBERON:0002119	75.45	gold quality
ganglionic eminence	UBERON:0004023	75.34	gold quality
spleen	UBERON:0002106	74.77	gold quality
embryo	UBERON:0000922	74.24	gold quality
germinal epithelium of ovary	UBERON:0001304	74.24	gold quality
calcaneal tendon	UBERON:0003701	74.22	gold quality
hindlimb stylopod muscle	UBERON:0004252	74.00	gold quality
lower lobe of lung	UBERON:0008949	73.41	silver quality
endocervix	UBERON:0000458	73.35	gold quality
right ovary	UBERON:0002118	73.21	gold quality
muscle of leg	UBERON:0001383	73.19	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	31.56
E-ANND-3	no	7.12
E-MTAB-5061	no	1.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

206 targeting ARHGAP28, 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-3162-3P	100.00	65.37	363
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4803	99.98	71.99	3117

Literature-anchored findings (GeneRIF, showing 2)

• The results of this study provide evidence that there are common variants within this protein that contribute to the risk for a general liability to substance dependence (PMID:24832863)
• these data suggest that the regulation of Rho by RhoGAPs, including Arhgap28, during the assembly and development of mechanically strong tissues is complex and may involve multiple RhoGAPs. (PMID:25211221)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgap28	ENSDARG00000101350
mus_musculus	Arhgap28	ENSMUSG00000024043
rattus_norvegicus	Arhgap28	ENSRNOG00000017065
drosophila_melanogaster	conu	FBGN0039994

Paralogs (3): ARHGAP40 (ENSG00000124143), ARHGAP18 (ENSG00000146376), ARHGAP19 (ENSG00000213390)

Protein

Protein identifiers

Rho GTPase-activating protein 28 — Q9P2N2 (reviewed: Q9P2N2)

Alternative names: Rho-type GTPase-activating protein 28

All UniProt accessions (8): Q9P2N2, E9PL26, E9PMX7, J3KT69, J3KTC0, J3QKM0, J3QLR3, J3QRC2

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. Expressed in testis. Expressed at moderate level in kidney and ovary, and weakly expressed in spleen and skeletal muscle.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9P2N2-1	1	yes
Q9P2N2-2	2
Q9P2N2-3	3
Q9P2N2-5	5

RefSeq proteins (4): NP_001010000, NP_001353159, NP_001353160, NP_001397802 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR057323	RHG40/28/18_ubiquitin	Domain

Pfam: PF00620, PF25442

UniProt features (23 total): compositionally biased region 5, splice variant 5, region of interest 4, sequence variant 3, modified residue 2, chain 1, domain 1, site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2N2-F1	73.63	0.47

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

Post-translational modifications (2): 72, 159

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8980692	RHOA GTPase cycle

MSigDB gene sets: 175 (showing top): ACTACCT_MIR196A_MIR196B, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, TATTATA_MIR374, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_BUNDLE_ASSEMBLY, GOBP_ACTIN_FILAMENT_ORGANIZATION, GOBP_ACTOMYOSIN_STRUCTURE_ORGANIZATION, GOBP_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_ACTIN_FILAMENT_BUNDLE_ASSEMBLY, CUI_TCF21_TARGETS_2_DN

GO Biological Process (4): signal transduction (GO:0007165), regulation of actin filament polymerization (GO:0030833), regulation of small GTPase mediated signal transduction (GO:0051056), negative regulation of stress fiber assembly (GO:0051497)

GO Molecular Function (1): GTPase activator activity (GO:0005096)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cell junction (GO:0030054)

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	4
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of actin polymerization or depolymerization	1
actin filament polymerization	1
regulation of protein polymerization	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
negative regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

943 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGAP28	AKAIN1	P0CW23	541
ARHGAP28	C10orf71	Q711Q0	512
ARHGAP28	L3MBTL4	Q8NA19	506
ARHGAP28	ARHGAP29	Q52LW3	476
ARHGAP28	ENOX1	Q8TC92	447
ARHGAP28	CNTROB	Q8N137	430
ARHGAP28	ANKRD12	Q6UB98	423
ARHGAP28	MAP6D1	Q9H9H5	421
ARHGAP28	SLC38A6	Q8IZM9	404
ARHGAP28	LIPN	Q5VXI9	404
ARHGAP28	CRYBB2	P43320	404
ARHGAP28	LAMA1	P25391	401
ARHGAP28	OR51V1	Q9H2C8	400
ARHGAP28	Q3SXR2	Q3SXR2	399
ARHGAP28	CRK	P46108	398
ARHGAP28	ZNF705B	P0CI00	398

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ARHGAP28	SLC25A5	psi-mi:“MI:0915”(physical association)	0.400
ARHGAP28	HSPB1	psi-mi:“MI:0915”(physical association)	0.370
MTNR1A	ARHGAP28	psi-mi:“MI:0915”(physical association)	0.000
ARHGAP28	MTNR1B	psi-mi:“MI:0915”(physical association)	0.000

ESM2 similar proteins: A0JPH7, A1A5Q0, B0R034, E1BTG2, E1C065, E1C760, F1MUG2, F7AEX0, G3XA57, O60308, P30306, P48966, Q02225, Q0IID7, Q0VBD2, Q14B46, Q28E45, Q28FA8, Q3UHZ5, Q4KM37, Q5EAW4, Q5FWH3, Q5JTW2, Q5RHY1, Q5XGX5, Q60949, Q6GQN0, Q6INA9, Q6NTY8, Q6NU40, Q6P5Q4, Q7L590, Q80U87, Q8BN58, Q8BXR9, Q8BZN6, Q8C5W4, Q8GT06, Q8K3X6, Q8N8V4

Diamond homologs: A2AB59, A2RUV4, A4IF90, A6NI28, A7E300, A7MB27, B2RQE8, B2RTY4, B9VTT2, D3ZZN9, E7EZG2, E7F3F0, E9Q6X9, O43182, O54834, O60890, O94988, P0CAX5, P15882, P34288, P35688, P46941, P52757, Q03070, Q07960, Q08DP6, Q10164, Q13459, Q14CB8, Q15311, Q17QN0, Q3KRB8, Q3TBD2, Q4LDD4, Q53QZ3, Q54C77, Q54FG5, Q54J98, Q54SL6, Q54TH9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ARHGAP28	“down-regulates activity”	RHOA	“gtpase-activating protein”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	94
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1330176	GRCh37/hg19 18p11.32-11.1(chr18:10501-15410398)x1	Pathogenic

SpliceAI

2551 predictions. Top by Δscore:

Variant	Effect	Δscore
18:6837195:A:AG	acceptor_gain	1.0000
18:6837196:G:GG	acceptor_gain	1.0000
18:6837361:GA:G	donor_gain	1.0000
18:6837379:G:T	donor_gain	1.0000
18:6837411:TCCT:T	donor_gain	1.0000
18:6837412:CCT:C	donor_gain	1.0000
18:6837415:G:GG	donor_gain	1.0000
18:6851032:A:AG	acceptor_gain	1.0000
18:6851033:G:GG	acceptor_gain	1.0000
18:6851033:GCCTC:G	acceptor_gain	1.0000
18:6868225:GCGA:G	donor_gain	1.0000
18:6868228:A:AG	donor_gain	1.0000
18:6868228:A:G	donor_gain	1.0000
18:6868232:GTG:G	donor_gain	1.0000
18:6870581:T:A	acceptor_gain	1.0000
18:6870585:TTTA:T	acceptor_loss	1.0000
18:6870586:TTAG:T	acceptor_loss	1.0000
18:6870587:TAG:T	acceptor_loss	1.0000
18:6870588:A:AG	acceptor_gain	1.0000
18:6870588:AGAT:A	acceptor_gain	1.0000
18:6870589:G:GT	acceptor_gain	1.0000
18:6870589:GA:G	acceptor_gain	1.0000
18:6870589:GAT:G	acceptor_gain	1.0000
18:6870589:GATG:G	acceptor_gain	1.0000
18:6870589:GATGA:G	acceptor_gain	1.0000
18:6870715:G:GT	donor_gain	1.0000
18:6870730:ACT:A	donor_gain	1.0000
18:6870730:ACTGT:A	donor_loss	1.0000
18:6870731:CTGTA:C	donor_loss	1.0000
18:6870732:TG:T	donor_loss	1.0000

AlphaMissense

4802 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:6912125:T:A	W721R	1.000
18:6912125:T:C	W721R	1.000
18:6876170:G:A	G418R	0.999
18:6876170:G:C	G418R	0.999
18:6876177:T:C	F420S	0.999
18:6882224:A:G	K460E	0.999
18:6882225:A:T	K460I	0.999
18:6882226:A:C	K460N	0.999
18:6882226:A:T	K460N	0.999
18:6889940:T:C	M530T	0.999
18:6896530:T:A	V645D	0.999
18:6912127:G:C	W721C	0.999
18:6912127:G:T	W721C	0.999
18:6837217:T:A	W116R	0.998
18:6837217:T:C	W116R	0.998
18:6837219:G:C	W116C	0.998
18:6837219:G:T	W116C	0.998
18:6876171:G:A	G418E	0.998
18:6876179:C:G	R421G	0.998
18:6876180:G:C	R421P	0.998
18:6876189:G:A	G424E	0.998
18:6882185:T:A	W447R	0.998
18:6882185:T:C	W447R	0.998
18:6889935:C:A	N528K	0.998
18:6889935:C:G	N528K	0.998
18:6912126:G:C	W721S	0.998
18:6837221:T:C	L117P	0.997
18:6873695:T:C	F378L	0.997
18:6873697:T:A	F378L	0.997
18:6873697:T:G	F378L	0.997

dbSNP variants (sampled 300 via entrez): RS1000002158 (18:6793780 G>C), RS1000055795 (18:6852041 T>G), RS1000064953 (18:6893364 G>T), RS1000070807 (18:6841515 T>C), RS1000085094 (18:6760224 A>G), RS1000092761 (18:6802476 G>C), RS1000142544 (18:6880454 C>T), RS1000146518 (18:6881773 A>G), RS1000174219 (18:6738865 C>T), RS1000181383 (18:6815708 G>A,C), RS1000190929 (18:6754856 A>G), RS1000195273 (18:6880729 G>T), RS1000197802 (18:6880187 A>G), RS1000222568 (18:6754646 T>C), RS1000226391 (18:6745151 A>C,G)

Disease associations

OMIM: gene MIM:610592 | disease phenotypes: MIM:146390

GenCC curated gene-disease

Mondo (1): chromosome 18p deletion syndrome (MONDO:0007800)

Orphanet (2): Monosomy 18p syndrome (Orphanet:1598), Partial deletion of the short arm of chromosome 18 syndrome (Orphanet:261974)

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001762_265	Obesity-related traits	4.000000e-06
GCST004490_8	Cerebrospinal fluid t-tau:AB1-42 ratio	8.000000e-08
GCST006138_38	Resting-state electroencephalogram vigilance	5.000000e-06
GCST007325_3	General risk tolerance (MTAG)	5.000000e-09
GCST007637_23	Diffusing capacity of carbon monoxide	4.000000e-06
GCST009391_1009	Metabolite levels	5.000000e-06
GCST009391_2031	Metabolite levels	9.000000e-06
GCST012341_7	Asparaginase hypersensitivity in acute lymphoblastic leukemia	9.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0005000	leptin measurement
EFO:0007708	t-tau:beta-amyloid 1-42 ratio measurement
EFO:0004357	electroencephalogram measurement
EFO:0008579	risk-taking behaviour
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0010359	lysophosphatidylcholine 18:0 measurement
EFO:0010371	lysophosphatidylethanolamine 22:6 measurement
EFO:0004881	asparaginase hypersensitivity

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538309	Chromosome 18p deletion syndrome (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
rs9958628	Toxicity	3	pegaspargase

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs9958628	ARHGAP28	3	1.25	1	pegaspargase

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	6
sodium arsenite	increases abundance, decreases expression, affects cotreatment	2
potassium chromate(VI)	affects cotreatment, decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, decreases methylation	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases methylation	1
trichostatin A	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sulforaphane	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	affects expression	1
cylindrospermopsin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
incobotulinumtoxinA	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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