ARHGDIA

Summary

ARHGDIA (Rho GDP dissociation inhibitor alpha, HGNC:678) is a protein-coding gene on chromosome 17q25.3, encoding Rho GDP-dissociation inhibitor 1 (P52565). Controls Rho proteins homeostasis.

This gene encodes a protein that plays a key role in the regulation of signaling through Rho GTPases. The encoded protein inhibits the disassociation of Rho family members from GDP (guanine diphosphate), thereby maintaining these factors in an inactive state. Activity of this protein is important in a variety of cellular processes, and expression of this gene may be altered in tumors. Mutations in this gene have been found in individuals with nephrotic syndrome, type 8. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 396 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephrotic syndrome, type 8 (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 93 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes
• MANE Select transcript: NM_004309

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:678
Approved symbol	ARHGDIA
Name	Rho GDP dissociation inhibitor alpha
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	RHOGDI
Ensembl gene	ENSG00000141522
Ensembl biotype	protein_coding
OMIM	601925
Entrez	396

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 12 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000269321, ENST00000400721, ENST00000541078, ENST00000578351, ENST00000579121, ENST00000580033, ENST00000580685, ENST00000581876, ENST00000582309, ENST00000582520, ENST00000582984, ENST00000583111, ENST00000583499, ENST00000583791, ENST00000583868, ENST00000584397, ENST00000584461, ENST00000877198, ENST00000877199, ENST00000877200, ENST00000877201

RefSeq mRNA: 7 — MANE Select: NM_004309 NM_001185077, NM_001185078, NM_001301240, NM_001301241, NM_001301242, NM_001301243, NM_004309

CCDS: CCDS11788, CCDS58609, CCDS77133

Canonical transcript exons

ENST00000269321 — 6 exons

Exon	Start	End
ENSE00001297309	81871298	81871337
ENSE00001370626	81867721	81869075
ENSE00001745599	81869330	81869406
ENSE00003593140	81869173	81869236
ENSE00003613800	81869741	81869957
ENSE00003636170	81869542	81869625

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 155.9321 / max 892.4886, expressed in 1827 samples.

FANTOM5 promoters (22 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168841	123.7272	1827
168825	4.8992	1565
168824	4.6562	1587
168831	3.8173	1470
168827	3.1725	1381
168822	2.1268	1191
168835	1.6499	1051
168836	1.5754	1053
168838	1.5351	1066
168837	1.2719	882

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.20	gold quality
colonic epithelium	UBERON:0000397	99.18	gold quality
mucosa of transverse colon	UBERON:0004991	99.15	gold quality
left uterine tube	UBERON:0001303	99.14	gold quality
upper lobe of left lung	UBERON:0008952	99.11	gold quality
right lung	UBERON:0002167	99.04	gold quality
ascending aorta	UBERON:0001496	99.03	gold quality
thoracic aorta	UBERON:0001515	99.03	gold quality
peripheral nervous system	UBERON:0000010	99.01	gold quality
nerve	UBERON:0001021	99.01	gold quality
tibial nerve	UBERON:0001323	99.01	gold quality
left coronary artery	UBERON:0001626	99.01	gold quality
metanephros cortex	UBERON:0010533	99.01	gold quality
adenohypophysis	UBERON:0002196	99.00	gold quality
right coronary artery	UBERON:0001625	98.97	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.97	gold quality
ectocervix	UBERON:0012249	98.97	gold quality
mucosa of stomach	UBERON:0001199	98.96	gold quality
omental fat pad	UBERON:0010414	98.94	gold quality
body of uterus	UBERON:0009853	98.93	gold quality
transverse colon	UBERON:0001157	98.92	gold quality
endocervix	UBERON:0000458	98.91	gold quality
lower esophagus mucosa	UBERON:0035834	98.91	gold quality
descending thoracic aorta	UBERON:0002345	98.89	gold quality
peritoneum	UBERON:0002358	98.89	gold quality
aorta	UBERON:0000947	98.88	gold quality
body of stomach	UBERON:0001161	98.88	gold quality
popliteal artery	UBERON:0002250	98.86	gold quality
tibial artery	UBERON:0007610	98.86	gold quality
coronary artery	UBERON:0001621	98.84	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.87
E-MTAB-6911	no	238.29
E-HCAD-8	no	41.35

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ESR1, ESR2, NFKB, PPM1F, SP1

miRNA regulators (miRDB)

68 targeting ARHGDIA, 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-1193	100.00	65.93	529
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325

Literature-anchored findings (GeneRIF, showing 40)

• analysis of inhibitory and shuttling functions of rhoGDI-3 and rhoGDI-1 (PMID:15513926)
• These results suggest that Src-mediated RhoGDI phosphorylation is a novel physiological mechanism for regulating Rho GTPase cytosol membrane-cycling and activity. (PMID:16943322)
• up-regulated in Crohn’s disease and ulcerative colitis patients (PMID:17330946)
• Underexpression of rho GDP dissociation inhibitor alpha is associated with oligodendroglioma (PMID:17653765)
• In addition to the activity of RhoGDI alpha in the cytoplasm, it also influences ER alpha signaling in the nucleus. (PMID:17909265)
• Bcr GTPase-activating domain activity is regulated through direct protein/protein interaction with the Rho guanine nucleotide dissociation inhibitor (PMID:18070886)
• in basal conditions, RhoGDIalpha is rate-limiting and the suppression of RhoA makes it available to stabilize RhoB (PMID:18524772)
• data suggest that RhoGDI may promote colorectal cancer progression and metastasis by stimulating tumor cell growth and migration (PMID:18651761)
• halothane binds to a site within the geranylgeranyl chain binding pocket of RhoGDIalpha, whereas alcohols bind to a distal site that interacts allosterically with this pocket. (PMID:18702520)
• Phosphorylation of GTP dissociation inhibitor by PKA negatively regulates RhoA. (PMID:18768928)
• morphological changes observed in Rab-GDI mutated patients, mainly localized in the cerebello-thalamo-prefrontal pathway, are consistent with the hypothesis that the cerebellum is one of the critical components of a global learning network (PMID:18992375)
• The gene ratio test with the COBLL1/ARHGDIA genes for survival of patients with malignant pleural mesothelioma has robust predictive value. (PMID:19401544)
• Rho-GDIalpha is possibly a useful biomarker to predict the response of breast cancer patients to CMF treatment. (PMID:20043072)
• Increased miR-151 expression due to gains on chromosome 8q24.3 can significantly promote hepatocellular carcinoma invasion/metastasis; meanwhile, upregulation of RhoGDIA, a direct and functional target of miR-151, inhibits migration/invasion. (PMID:20305651)
• This protein has been found differentially expressed in the anterior cingulate cortex from patients with schizophrenia (PMID:20381070)
• Because RhoGDI1 levels are limiting, and Rho proteins compete for binding to RhoGDI1, overexpression of an exogenous Rho GTPase displaces endogenous Rho proteins bound to RhoGDI1, inducing their degradation and inactivation (PMID:20400958)
• PKC phosphorylates RhoGDIalpha on serine 34, resulting in a specific decrease in affinity for RhoA but not Rac1 or Cdc42. (PMID:20472934)
• Data represent a novel signaling of semaphorin 5A and plexin B3 in the control of cell motility by indirect inactivation of Rac1 through RhoGDIalpha. (PMID:20696765)
• A network consisting of ezrin, RhoGDI1, RhoA, F-actin and membrane proteins functions to influence the modifications that occur on the membrane of the sperm head during human sperm capacitation. (PMID:20711218)
• The authors show here that the endocytic pathway followed by Clostridium perfringens Iota and Clostridium botulinum C2 toxins is independent of clathrin but requires the activity of dynamin and is regulated by Rho-GDI. (PMID:20846184)
• Both the mRNA and protein expressions of Rho-GDI in the decidual tissues were significantly higher in the normal pregnancy group than in the two severe preeclampsia groups. (PMID:21269984)
• Data show that knockdown of S100P led to downregulation of thioredoxin 1 and beta-tubulin and upregulation of RhoGDIA, all potential therapeutic targets in cancer. (PMID:21327297)
• XIAP was found to negatively regulate RhoGDI SUMOylation, which might affect its activity in controlling cell motility (PMID:21402697)
• Loss of Rho GDIalpha enhances metastasis and resistance to tamoxifen via effects on both ERalpha and MTA2 in models of ERalpha-positive breast cancer and in tumors of tamoxifen-treated patients. (PMID:21447808)
• The RhoGDIalpha protein is located in the acrosome and flagellum of human sperm, and might be involved in sperm movement, capacitation and acrosome reaction. (PMID:21548210)
• We provide evidence that ARHGDIA, COBLL1, and TM4SF1 are negative regulators of apoptosis in cultured tumor cells. (PMID:21569526)
• Loss of GDIalpha expression promotes the development and progression of prostate cancer. (PMID:21681778)
• The physiological regulation of RhoGDI SUMOylation by the RING domain of XIAP may account for modulation of cancer cell invasion and metastasis by XIAP (PMID:22393046)
• Rho GDI may be useful as a diagnostic biomarker and/or a therapeutic to prevent colon and prostate cancer metastasis (PMID:22530308)
• demonstrate that membrane extraction of Rho GTPase by RhoGDI is a thermodynamically favored passive process that operates through a series of progressively tighter intermediates, much like the one that is mediated by RabGDI (PMID:22628549)
• Knockdown of RhoGDIalpha induces apoptosis and increases lung cancer cell chemosensitivity to paclitaxel. (PMID:22668020)
• Prenylated and palmitoylated brain Cdc42 did not interact with RhoGDIalpha. (PMID:23358418)
• Mutations in ARHGDIA need to be considered in the aetiology of heritable forms of nephrotic syndrome. (PMID:23434736)
• It was found that the silencing of RhoGDIalpha in MCF7 and MDA-MB-231 cells significantly increased migration and invasion of these cells into the lower surface of porous membrane of the transwell chambers. (PMID:23563506)
• ARHGDIA mutations (R120X and G173V) from individuals with nephrotic syndrome abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA. (PMID:23867502)
• we demonstrated the regulation of targeting/accumulation of the RhoGDIalpha-Rac1 complex to phagosomes (PMID:23918979)
• the association of RhoGDIalpha with TROY contributed to TROY-dependent RhoA activation and neurite outgrowth inhibition after Nogo-66 stimulation. (PMID:24129566)
• A significant trend was identified between loss of RhoGDI expression in hepatocellular carcinoma and worsening clinical prognosis. (PMID:24228117)
• new mechanistic insights into the understanding of essential role of SUMOylation at Lys-138 in RhoGDIalpha’s biological function. (PMID:24342356)
• Our findings suggest that RhoGDI overexpression is a predictor of distant metastasis and plays an important role in the progression of hepatocellular carcinoma (PMID:24374343)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgdia	ENSDARG00000043795
mus_musculus	Arhgdia	ENSMUSG00000025132
rattus_norvegicus	Arhgdia	ENSRNOG00000036688
drosophila_melanogaster	RhoGDI	FBGN0036921
caenorhabditis_elegans		WBGENE00004356

Paralogs (2): ARHGDIB (ENSG00000111348), ARHGDIG (ENSG00000242173)

Protein

Protein identifiers

Rho GDP-dissociation inhibitor 1 — P52565 (reviewed: P52565)

Alternative names: Rho-GDI alpha

All UniProt accessions (7): P52565, J3KRE2, J3KRY1, J3KS60, J3KTF8, J3QQX2, V9HWE8

UniProt curated annotations — full annotation on UniProt →

Function. Controls Rho proteins homeostasis. Regulates the GDP/GTP exchange reaction of the Rho proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them. Retains Rho proteins such as CDC42, RAC1 and RHOA in an inactive cytosolic pool, regulating their stability and protecting them from degradation. Actively involved in the recycling and distribution of activated Rho GTPases in the cell, mediates extraction from membranes of both inactive and activated molecules due its exceptionally high affinity for prenylated forms. Through the modulation of Rho proteins, may play a role in cell motility regulation. In glioma cells, inhibits cell migration and invasion by mediating the signals of SEMA5A and PLXNB3 that lead to inactivation of RAC1.

Subunit / interactions. Monomer. Interacts with FER. Interacts with PLXNB3. Forms a heterodimer with RAC1. Interacts with RHOA, the affinity is increased by three orders of magnitude when RHOA is prenylated. Interacts with PSMD10; the interaction increases ARHGDIA association with RHOA, leading to ARHGDIA-mediated inactivation of RHOA and ROCK and prolonged AKT activation. Interacts with KANK2; the interaction is direct and may regulate the interaction of ARHGDIA with RHOA, RAC1 and CDC42. Interacts with RHOC. Interacts with CDC42. Interacts with NGFR (via death domain); NGFR binding decreases the affinity for RHOA.

Subcellular location. Cytoplasm.

Disease relevance. Nephrotic syndrome 8 (NPHS8) [MIM:615244] A form of nephrotic syndrome, a renal disease clinically characterized by progressive renal failure, severe proteinuria, hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show diffuse mesangial sclerosis, with small glomeruli, hypercellularity, increased extracellular matrix, and contracted/collapsed glomerular tufts surrounded by immature or abnormal podocytes. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Rho GDI family.

Isoforms (2)

UniProt ID	Names	Canonical?
P52565-1	1	yes
P52565-2	2

RefSeq proteins (7): NP_001172006, NP_001172007, NP_001288169, NP_001288170, NP_001288171, NP_001288172, NP_004300* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000406	Rho_GDI	Family
IPR014756	Ig_E-set	Homologous_superfamily
IPR024792	RhoGDI_dom_sf	Homologous_superfamily

Pfam: PF02115

UniProt features (45 total): strand 12, modified residue 9, helix 5, cross-link 4, mutagenesis site 4, turn 4, sequence conflict 2, initiator methionine 1, chain 1, splice variant 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
1KMT	X-RAY DIFFRACTION	1.3
1QVY	X-RAY DIFFRACTION	1.6
2JHX	X-RAY DIFFRACTION	1.6
2JHU	X-RAY DIFFRACTION	1.65
2JHT	X-RAY DIFFRACTION	1.88
2JHY	X-RAY DIFFRACTION	1.9
2JHS	X-RAY DIFFRACTION	1.95
1FSO	X-RAY DIFFRACTION	2
2JHV	X-RAY DIFFRACTION	2.07
2JI0	X-RAY DIFFRACTION	2.1
2JHZ	X-RAY DIFFRACTION	2.2
2BXW	X-RAY DIFFRACTION	2.4
1RHO	X-RAY DIFFRACTION	2.5
2JHW	X-RAY DIFFRACTION	2.5
1FT0	X-RAY DIFFRACTION	2.6
1FST	X-RAY DIFFRACTION	2.7
1HH4	X-RAY DIFFRACTION	2.7
1FT3	X-RAY DIFFRACTION	2.8
1CC0	X-RAY DIFFRACTION	5
2N80	SOLUTION NMR
8X8T	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52565-F1	90.62	0.77

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 (13): 141, 178, 138, 138, 141, 141, 2, 34, 43, 47, 105, 127, 141

Mutagenesis-validated functional residues (4):

Position	Phenotype
45	loss of rhoa interaction; when associated with a-185.
99	loss of interaction with ngfr.
185	loss of rhoa interaction; when associated with a-45.
199	loss of interaction with ngfr.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-193634	Axonal growth inhibition (RHOA activation)
R-HSA-209563	Axonal growth stimulation
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013407	RHOH GTPase cycle
R-HSA-9013408	RHOG GTPase cycle

MSigDB gene sets: 299 (showing top): GGGACCA_MIR133A_MIR133B, ELVIDGE_HYPOXIA_DN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, ENK_UV_RESPONSE_KERATINOCYTE_UP, DAZARD_UV_RESPONSE_CLUSTER_G4, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, HINATA_NFKB_TARGETS_KERATINOCYTE_UP, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOBP_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, JIANG_TIP30_TARGETS_DN, WEIGEL_OXIDATIVE_STRESS_RESPONSE, SENESE_HDAC1_TARGETS_UP, GRUETZMANN_PANCREATIC_CANCER_UP

GO Biological Process (6): Rho protein signal transduction (GO:0007266), regulation of protein localization (GO:0032880), regulation of Rho protein signal transduction (GO:0035023), negative regulation of apoptotic process (GO:0043066), semaphorin-plexin signaling pathway (GO:0071526), regulation of synaptic vesicle cycle (GO:0098693)

GO Molecular Function (3): Rho GDP-dissociation inhibitor activity (GO:0005094), GTPase activator activity (GO:0005096), protein binding (GO:0005515)

GO Cellular Component (8): immunological synapse (GO:0001772), nucleus (GO:0005634), cytosol (GO:0005829), cytoskeleton (GO:0005856), membrane (GO:0016020), extracellular exosome (GO:0070062), Schaffer collateral - CA1 synapse (GO:0098685), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RHO GTPase cycle	7
p75NTR regulates axonogenesis	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
small GTPase-mediated signal transduction	1
intracellular protein localization	1
regulation of localization	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cell surface receptor signaling pathway	1
regulation of vesicle-mediated transport	1
synaptic vesicle cycle	1
GDP-dissociation inhibitor activity	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
binding	1
plasma membrane	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular membraneless organelle	1
extracellular vesicle	1
synapse	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGDIA	RHOA	P06749	997
ARHGDIA	CDC42	P21181	996
ARHGDIA	AKT1	P31749	982
ARHGDIA	RAC2	P15153	939
ARHGDIA	KANK2	Q63ZY3	849
ARHGDIA	NGFR	P08138	822
ARHGDIA	RHOC	P08134	812
ARHGDIA	RHOG	P35238	796
ARHGDIA	RAC1	P15154	773
ARHGDIA	RHOB	P01121	757
ARHGDIA	DGKZ	Q13574	729
ARHGDIA	ARHGAP1	Q07960	693
ARHGDIA	RDX	P35241	693
ARHGDIA	EFNB1	P98172	692
ARHGDIA	ARHGEF7	Q14155	686

IntAct

122 interactions, top by confidence:

A	B	Type	Score
RAC1	ARHGDIA	psi-mi:“MI:0407”(direct interaction)	0.930
ARHGDIA	RAC1	psi-mi:“MI:0915”(physical association)	0.930
RAC1	ARHGDIA	psi-mi:“MI:0915”(physical association)	0.930
RHOA	ARHGDIA	psi-mi:“MI:0915”(physical association)	0.860
ARHGDIA	RHOA	psi-mi:“MI:0407”(direct interaction)	0.860
ARHGDIA	RHOA	psi-mi:“MI:0915”(physical association)	0.860
ARHGDIA	CDC42	psi-mi:“MI:0915”(physical association)	0.760
RHOC	RAP1GDS1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RAC1	COX6C	psi-mi:“MI:0914”(association)	0.640
ARHGDIA	RAC3	psi-mi:“MI:0915”(physical association)	0.550
ARHGDIA	RDX	psi-mi:“MI:0915”(physical association)	0.540
RDX	ARHGDIA	psi-mi:“MI:0407”(direct interaction)	0.540
ARHGDIA	TINF2	psi-mi:“MI:0915”(physical association)	0.510
TNFRSF19	ARHGDIA	psi-mi:“MI:0915”(physical association)	0.460
TNFRSF19	ARHGDIA	psi-mi:“MI:0403”(colocalization)	0.460
EZR	ARHGDIA	psi-mi:“MI:0403”(colocalization)	0.460
ARHGDIA	EZR	psi-mi:“MI:0915”(physical association)	0.460
ARHGDIA	RAC1	psi-mi:“MI:0407”(direct interaction)	0.440
LMTK3	GPI	psi-mi:“MI:0914”(association)	0.420
Ngfr	ARHGDIA	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (272): ARHGDIA (Two-hybrid), ARHGDIA (Affinity Capture-MS), ARHGDIA (Affinity Capture-MS), ARHGDIA (Affinity Capture-MS), ALDOA (Co-fractionation), ARHGDIA (Co-fractionation), ARHGDIA (Co-fractionation), ARHGDIA (Co-fractionation), ARHGDIA (Co-fractionation), ARHGDIA (Co-fractionation), ARHGDIA (Co-fractionation), ARHGDIA (Co-fractionation), ARHGDIA (Co-fractionation), ARHGDIA (Co-fractionation), ARHGDIA (Co-fractionation)

ESM2 similar proteins: A2VE01, A4F4L4, O70133, O88761, O94973, O96015, P17427, P18484, P19803, P35615, P38024, P48444, P52565, P53619, P62495, P62496, P62497, P62498, Q08211, Q0VCK5, Q0VCX5, Q1W375, Q28141, Q32KN5, Q3TXS7, Q4R4J0, Q4R7R3, Q5F418, Q5R4C7, Q5R5S4, Q5R874, Q5RA77, Q5U2Q7, Q5XI73, Q5XJY5, Q5ZJL4, Q5ZL57, Q66H80, Q68FK8, Q6NRT5

Diamond homologs: O14224, P19803, P52565, P52566, P80237, Q0II80, Q12434, Q20496, Q4R4J0, Q5XI73, Q61599, Q62160, Q95UQ1, Q99819, Q99PT1, Q9SFC6, Q9TU03

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
PAK1	down-regulates	ARHGDIA	phosphorylation
SRC	down-regulates	ARHGDIA	phosphorylation
PRKACA	down-regulates	ARHGDIA	phosphorylation
RNF128	“up-regulates quantity by stabilization”	ARHGDIA	polyubiquitination
PTPN12	“up-regulates activity”	ARHGDIA	dephosphorylation
PLK1	“up-regulates activity”	ARHGDIA	phosphorylation
FER	“down-regulates activity”	ARHGDIA	phosphorylation
PRKCA	“down-regulates activity”	ARHGDIA	phosphorylation
PRKCZ	“up-regulates activity”	ARHGDIA	phosphorylation
PLXNB3	“up-regulates activity”	ARHGDIA	binding
ARHGDIA	“down-regulates activity”	RAC1	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 108 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
RHO GTPases activate CIT	5	39.5×	4e-05
GPVI-mediated activation cascade	7	28.4×	2e-06
RHO GTPases activate PKNs	5	20.9×	6e-04
Signaling by BRAF and RAF1 fusions	5	11.2×	5e-03
MAPK6/MAPK4 signaling	6	10.7×	2e-03
MAPK family signaling cascades	6	8.1×	5e-03
RHO GTPase Effectors	7	6.3×	5e-03
Diseases of signal transduction by growth factor receptors and second messengers	8	6.0×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of cell polarity	5	21.6×	7e-04
regulation of actin cytoskeleton organization	9	15.2×	8e-06
positive regulation of protein catabolic process	5	10.9×	6e-03
actin filament organization	8	10.2×	3e-04
regulation of cell migration	6	10.2×	3e-03
small GTPase-mediated signal transduction	5	9.8×	8e-03
regulation of cell shape	6	7.9×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	38
Likely benign	34
Benign	4

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
140593	NM_004309.6(ARHGDIA):c.518G>T (p.Gly173Val)	Pathogenic
140594	NM_004309.6(ARHGDIA):c.358C>T (p.Arg120Ter)	Pathogenic
3769217	NC_000017.10:g.(?79825596)(79828874_?)del	Pathogenic
50501	NM_004309.6(ARHGDIA):c.547GAC[2] (p.Asp185del)	Pathogenic
3064694	NM_004309.6(ARHGDIA):c.*167dup	Likely pathogenic

SpliceAI

728 predictions. Top by Δscore:

Variant	Effect	Δscore
17:81869071:GTCAA:G	acceptor_gain	1.0000
17:81869072:TCAA:T	acceptor_gain	1.0000
17:81869073:CAA:C	acceptor_gain	1.0000
17:81869073:CAAC:C	acceptor_gain	1.0000
17:81869074:AA:A	acceptor_gain	1.0000
17:81869075:AC:A	acceptor_loss	1.0000
17:81869076:C:CA	acceptor_loss	1.0000
17:81869076:C:CC	acceptor_gain	1.0000
17:81869077:T:A	acceptor_loss	1.0000
17:81869080:G:T	acceptor_gain	1.0000
17:81869082:C:CT	acceptor_gain	1.0000
17:81869167:A:AC	donor_gain	1.0000
17:81869168:C:CC	donor_gain	1.0000
17:81869168:CTCA:C	donor_gain	1.0000
17:81869169:TCACT:T	donor_loss	1.0000
17:81869170:CA:C	donor_loss	1.0000
17:81869171:A:AC	donor_gain	1.0000
17:81869171:ACT:A	donor_gain	1.0000
17:81869171:ACTC:A	donor_loss	1.0000
17:81869172:C:CC	donor_gain	1.0000
17:81869172:CT:C	donor_gain	1.0000
17:81869172:CTC:C	donor_gain	1.0000
17:81869185:T:A	donor_gain	1.0000
17:81869235:ACC:A	acceptor_loss	1.0000
17:81869237:C:CC	acceptor_gain	1.0000
17:81869237:CTGCA:C	acceptor_loss	1.0000
17:81869325:CTTA:C	donor_loss	1.0000
17:81869326:TTA:T	donor_loss	1.0000
17:81869327:TA:T	donor_loss	1.0000
17:81869328:A:AC	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000404602 (17:81867742 C>T), RS1000866967 (17:81867984 G>T), RS1000922657 (17:81871257 C>G), RS1000990210 (17:81872395 T>C,G), RS1001205382 (17:81872652 G>T), RS1001257609 (17:81872888 A>G), RS1002088850 (17:81870733 C>T), RS1002368459 (17:81868173 A>C), RS1002829449 (17:81868342 G>A), RS1002883021 (17:81872682 A>G), RS1002992620 (17:81870068 C>G,T), RS1002997795 (17:81872481 A>C), RS1003327596 (17:81868483 G>A,T), RS1003613126 (17:81868702 C>T), RS1004492781 (17:81869587 G>A)

Disease associations

OMIM: gene MIM:601925 | disease phenotypes: MIM:615244, MIM:256300

GenCC curated gene-disease

Disease	Classification	Inheritance
nephrotic syndrome, type 8	Strong	Autosomal recessive
familial idiopathic steroid-resistant nephrotic syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nephrotic syndrome, type 8	Moderate	AR

Mondo (4): nephrotic syndrome, type 8 (MONDO:0014099), congenital nephrotic syndrome, Finnish type (MONDO:0009732), chronic kidney disease (MONDO:0005300), familial idiopathic steroid-resistant nephrotic syndrome (MONDO:0019006)

Orphanet (2): Hereditary steroid-resistant nephrotic syndrome (Orphanet:656), Congenital nephrotic syndrome, Finnish type (Orphanet:839)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000100	Nephrotic syndrome
HP:0000407	Sensorineural hearing impairment
HP:0000707	Abnormality of the nervous system
HP:0000737	Irritability
HP:0000969	Edema
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001945	Fever
HP:0001967	Diffuse mesangial sclerosis
HP:0002027	Abdominal pain
HP:0002315	Headache
HP:0002586	Peritonitis
HP:0003073	Hypoalbuminemia
HP:0003623	Neonatal onset
HP:0003678	Rapidly progressive
HP:0003774	Stage 5 chronic kidney disease
HP:0007430	Generalized edema
HP:0011947	Respiratory tract infection
HP:0012577	Thin glomerular basement membrane
HP:0012579	Minimal change glomerulonephritis
HP:0012622	Chronic kidney disease
HP:0031504	Foamy urine
HP:0100539	Periorbital edema
HP:0100704	Cerebral visual impairment

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3638327 (SINGLE PROTEIN)

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

ChEMBL bioactivities

6 potent at pChembl≥5 of 8 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.46	Ki	35	nM	CHEMBL3647977
7.23	Ki	59	nM	CHEMBL3647976
7.14	Ki	72	nM	CHEMBL3647974
7.04	Ki	91	nM	CHEMBL3647975
6.09	Ki	806	nM	CHEMBL5847637
6.01	Ki	976	nM	CHEMBL3647979

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases expression	5
sodium arsenite	increases abundance, increases expression, decreases expression	4
bisphenol A	affects expression, increases expression	3
Air Pollutants	affects expression, increases abundance, decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression, increases methylation, decreases reaction	3
Tobacco Smoke Pollution	affects expression, increases expression, increases metabolic processing	3
Acetaminophen	increases expression, decreases expression	2
Cadmium	increases expression	2
Cisplatin	decreases expression, increases reaction	2
Diethylstilbestrol	increases expression, decreases expression	2
Doxorubicin	affects reaction, increases activity, affects response to substance, increases expression	2
Estradiol	decreases expression	2
Nickel	increases expression	2
Valproic Acid	affects expression, increases expression	2
Genistein	decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
beauvericin	decreases expression	1
daidzein	decreases expression	1
naringenin	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
decabromobiphenyl ether	decreases expression	1
ferric ammonium citrate	decreases reaction, increases expression	1
beta-lapachone	increases expression	1
pyrrolidine dithiocarbamic acid	decreases expression, affects cotreatment, increases expression	1
nonylphenol	decreases expression	1
manganese chloride	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3705256	Binding	Inhibition Assay: Inhibition of Rho kinase 2 and Rho kinase 1 activity was determined using the IMAP™ Screening Express Kit (Molecular Devices product number #8073). Rho kinase 2 enzyme (Upstate/Chemicon #14-451), Rho kinase 1 (Upstate/Chem	Bridged bicyclic RHO kinase inhibitor compounds, composition and use

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2S1	Abcam HEK293T ARHGDIA KO 1	Transformed cell line	Female
CVCL_B2S2	Abcam HEK293T ARHGDIA KO 2	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00073710	PHASE4	COMPLETED	Study to Evaluate the Effects of Zemplar Injection and Calcijex on Intestinal Absorption of Calcium
NCT00125593	PHASE4	COMPLETED	Study of Heart and Renal Protection
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00155246	PHASE4	COMPLETED	Efficacy of Pentoxifylline on Chronic Kidney Disease
NCT00175149	PHASE4	TERMINATED	Active Vitamin D Effect on Left Ventricular Hypertrophy
NCT00184769	PHASE4	COMPLETED	Growth Hormone Treatment in Infants Aged 1 to 2 Years With Chronic Renal Insufficiency (CRI) and Growth Retardation.
NCT00190580	PHASE4	COMPLETED	Kanagawa Valsartan Trial (KVT): Effects of Valsartan on Renal and Cardiovascular Disease
NCT00194961	PHASE4	TERMINATED	Effect of Growth Hormone on Leptin, Cytokines and Body Composition of Children With Growth Failure Due to Chronic Kidney Disease
NCT00239642	PHASE4	COMPLETED	Safety and Efficacy of Iron Sucrose in Children
NCT00324571	PHASE4	COMPLETED	Dialysis Clinical Outcomes Revisited (DCOR) Trial
NCT00364884	PHASE4	UNKNOWN	Keto-/Amino Acid Supplemented Low Protein Diet in Patients With Chronic Kidney Disease
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00384618	PHASE4	TERMINATED	Anti-Oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study
NCT00478543	PHASE4	COMPLETED	Loop Diuretics in Chronic Kidney Disease
NCT00632125	PHASE4	COMPLETED	Post-authorization Safety Study in CKD Subjects Receiving HX575 i.v.
NCT00644046	PHASE4	COMPLETED	Chronic Kidney Disease Prevention of An-Lo District, Keelung
NCT00719316	PHASE4	UNKNOWN	Aliskiren and Muscle Sympathetic Nerve Activity
NCT00725517	PHASE4	COMPLETED	Efficacy and Safety of a 7.5% Icodextrin Peritoneal Dialysis Solution in Once-Daily Long Dwell Exchange
NCT00741585	PHASE4	COMPLETED	Prognostic Value of the Circadian Pattern of Ambulatory Blood Pressure for Multiple Risk Assessment
NCT00749736	PHASE4	COMPLETED	The Role of Vitamin D in Immune Function in Patients With Chronic Kidney Disease (CKD) Stages 3 and 4.
NCT00752102	PHASE4	COMPLETED	Vitamin D and Coronary Calcification Study
NCT00756145	PHASE4	COMPLETED	The Use of Low Molecular Weight Heparin in Hemodiafiltration
NCT00768638	PHASE4	COMPLETED	Study of Atorvastatin Dose Dependent Reduction of Proteinuria
NCT00786136	PHASE4	COMPLETED	Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes
NCT00803712	PHASE4	COMPLETED	20070360 Incident Dialysis
NCT00812123	PHASE4	COMPLETED	Calcineurin Free Immunosuppression in Renal Transplant Recipients
NCT00823303	PHASE4	COMPLETED	Paricalcitol Versus Calcitriol for Efficacy and Safety in Stage 3/4 Chronic Kidney Disease (CKD) With Secondary Hyperparathyroidism (SHPT)
NCT00830037	PHASE4	TERMINATED	A Clinical Trial of Oral Versus IV Iron in Patients With Chronic Kidney Disease
NCT00852969	PHASE4	COMPLETED	Niacin and Endothelial Function in Early CKD
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
NCT00860431	PHASE4	COMPLETED	Kremezin Study Against Renal Disease Progression in Korea
NCT00882401	PHASE4	COMPLETED	Vitamin D, Chronic Kidney Disease (CKD) and the Microcirculation
NCT00889629	PHASE4	COMPLETED	Pilot Study Evaluating Doxercalciferol Replacement Therapy in Kidney Transplant Recipients
NCT00892892	PHASE4	WITHDRAWN	Sympathetic Nerve Activity in Renal Failure
NCT00893425	PHASE4	COMPLETED	Effect of Renin Angiotensin System Blockade on the Fas Antigen (CD95) and Asymmetric Dimethylarginine (ADMA) Levels in Type-2 Diabetic Patients With Proteinuria
NCT00908310	PHASE4	COMPLETED	Post-marketing Safety Study in Patients With Moderate Renal Insufficiency Who Receive Omniscan for Contrast-enhanced Magnetic Resonance Imaging (MRI)
NCT00958451	PHASE4	COMPLETED	Vitamin D Deficiency in Chronic Kidney Disease (CKD) Patients