ARHGEF1

Summary

ARHGEF1 (Rho guanine nucleotide exchange factor 1, HGNC:681) is a protein-coding gene on chromosome 19q13.2, encoding Rho guanine nucleotide exchange factor 1 (Q92888). Seems to play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13) subunits.

Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form complex with G proteins and stimulate Rho-dependent signals. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been defined.

Source: NCBI Gene 9138 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 62 (Moderate, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 960 total — 1 likely-pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes
• MANE Select transcript: NM_004706

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:681
Approved symbol	ARHGEF1
Name	Rho guanine nucleotide exchange factor 1
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	P115-RHOGEF, SUB1.5, LBCL2
Ensembl gene	ENSG00000076928
Ensembl biotype	protein_coding
OMIM	601855
Entrez	9138

Gene structure

Transcript identifiers

Ensembl transcripts: 64 — 49 protein_coding, 9 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000337665, ENST00000347545, ENST00000354532, ENST00000378152, ENST00000593609, ENST00000594044, ENST00000594258, ENST00000594417, ENST00000594513, ENST00000594521, ENST00000595723, ENST00000595770, ENST00000595897, ENST00000596957, ENST00000598444, ENST00000598587, ENST00000598812, ENST00000599589, ENST00000599846, ENST00000600274, ENST00000600387, ENST00000600517, ENST00000617585, ENST00000698932, ENST00000698933, ENST00000698934, ENST00000706938, ENST00000854345, ENST00000854346, ENST00000854347, ENST00000854348, ENST00000854349, ENST00000854350, ENST00000854351, ENST00000854352, ENST00000854353, ENST00000854354, ENST00000854355, ENST00000854356, ENST00000854357, ENST00000854358, ENST00000854359, ENST00000938777, ENST00000938778, ENST00000938779, ENST00000938780, ENST00000938781, ENST00000938782, ENST00000938783, ENST00000938784, ENST00000953275, ENST00000953276, ENST00000953277, ENST00000953278, ENST00000953279, ENST00000953280, ENST00000953281, ENST00000953282, ENST00000953283, ENST00000953284, ENST00000953285, ENST00000953286, ENST00000953287, ENST00000953288

RefSeq mRNA: 8 — MANE Select: NM_004706 NM_001396000, NM_001396002, NM_001396003, NM_001396004, NM_001396006, NM_004706, NM_198977, NM_199002

CCDS: CCDS12590, CCDS12591, CCDS12592, CCDS92626

Canonical transcript exons

ENST00000354532 — 29 exons

Exon	Start	End
ENSE00002226231	41892331	41892373
ENSE00002287830	41892025	41892123
ENSE00003466456	41902533	41902658
ENSE00003483597	41892603	41892849
ENSE00003495257	41905939	41906025
ENSE00003501780	41888752	41888865
ENSE00003529551	41904216	41904383
ENSE00003536779	41894626	41894661
ENSE00003538676	41903707	41903784
ENSE00003542534	41895349	41895486
ENSE00003543569	41905760	41905827
ENSE00003555357	41893274	41893303
ENSE00003560590	41902274	41902356
ENSE00003566193	41894207	41894306
ENSE00003590431	41902784	41902898
ENSE00003596366	41901887	41902033
ENSE00003601475	41903307	41903407
ENSE00003604432	41896377	41896482
ENSE00003610539	41888192	41888278
ENSE00003614755	41888064	41888106
ENSE00003627124	41906457	41906620
ENSE00003641653	41904035	41904110
ENSE00003642613	41904949	41905036
ENSE00003660838	41905175	41905261
ENSE00003669093	41894451	41894547
ENSE00003671877	41906703	41906803
ENSE00003685182	41898442	41898587
ENSE00003900830	41883184	41883289
ENSE00003902719	41907105	41907452

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 99.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.2234 / max 3882.3254, expressed in 1814 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176086	33.4251	1783
176090	3.6675	1422
176095	0.8450	126
176088	0.6082	168
176087	0.5748	117
176092	0.4077	99
176089	0.3748	135
176093	0.1884	73
176104	0.0901	50
176094	0.0417	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.58	gold quality
lymph node	UBERON:0000029	98.74	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.40	gold quality
upper lobe of left lung	UBERON:0008952	98.40	gold quality
right lung	UBERON:0002167	98.37	gold quality
spleen	UBERON:0002106	98.30	gold quality
metanephros cortex	UBERON:0010533	97.97	gold quality
right uterine tube	UBERON:0001302	97.93	gold quality
cardia of stomach	UBERON:0001162	97.87	gold quality
monocyte	CL:0000576	97.76	gold quality
right lobe of thyroid gland	UBERON:0001119	97.75	gold quality
lower esophagus mucosa	UBERON:0035834	97.67	gold quality
left uterine tube	UBERON:0001303	97.62	gold quality
body of stomach	UBERON:0001161	97.57	gold quality
leukocyte	CL:0000738	97.56	gold quality
endocervix	UBERON:0000458	97.53	gold quality
mononuclear cell	CL:0000842	97.52	gold quality
left lobe of thyroid gland	UBERON:0001120	97.50	gold quality
omental fat pad	UBERON:0010414	97.43	gold quality
peritoneum	UBERON:0002358	97.42	gold quality
transverse colon	UBERON:0001157	97.41	gold quality
right ovary	UBERON:0002118	97.40	gold quality
fundus of stomach	UBERON:0001160	97.39	gold quality
pylorus	UBERON:0001166	97.33	gold quality
body of uterus	UBERON:0009853	97.31	gold quality
mucosa of stomach	UBERON:0001199	97.29	gold quality
apex of heart	UBERON:0002098	97.27	gold quality
minor salivary gland	UBERON:0001830	97.26	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.19	gold quality
tibial nerve	UBERON:0001323	97.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	28.51
E-ANND-3	yes	12.04

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HOXA5, HOXA9

miRNA regulators (miRDB)

27 targeting ARHGEF1, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-6835-5P	95.81	64.27	500

Literature-anchored findings (GeneRIF, showing 27)

• coexpression of a dominant negative PDZ-RhoGEF abrogated the ability of plexin-B1 to cause stress fiber formation (PMID:12372594)
• rgRGS domain may serve a structural or allosteric role in the regulation of the nucleotide exchange activity of p115RhoGEF on Rho by Galpha(13) (PMID:12525488)
• CD44 interaction with p115RhoGEF and ROK plays a pivotal role in promoting Gab-1 phosphorylation leading to Gab-1.PI 3-kinase membrane localization, AKT signaling, and cytokine (M-CSF) production during HA-mediated breast cancer progression (PMID:12748184)
• data demonstrate a pathway of Rho activation involving protein kinase c alpha-dependent phosphorylation of p115Rho guanine exchange factor (PMID:12754211)
• Data show that different rho guanine nucleotide exchange factors (rhoGEFs; p115rhoGEF, LARG and PDZrhoGEF) mediate downstream rho signaling by the thrombin and lysophosphatidic acid receptors. (PMID:15143072)
• Several features of a typical alpha/RGS interaction are preserved in the alpha(13)/p115RhoGEF interaction. (PMID:15735747)
• analysis of a novel cross-talk exerted from the LPA/Galpha(13)/p115RhoGEF/RhoA pathway to the beta(2)-adrenergic receptor/Galpha(s)/adenylyl cyclase pathway (PMID:17493936)
• A pronounced and rapid translocation of p115-RhoGEF from the cytosol to the plasma membrane was observed upon activation of several G(12/13)-coupled receptors in a cell type-independent fashion. (PMID:18320579)
• Data show that microtubules in neighboring cells reorient and target p115 RhoGEF to sites where dying cells are squeezed out of the epithelial sheet. (PMID:19720875)
• ARHGEF1 is involed in hypertension by controlling its molecular mechanisms. (PMID:20619149)
• The linker region connecting the N-terminal RGS-homology domain and the Dbl homology domain inhibits the intrinsic guanine nucleotide exchange activity of p115. (PMID:21064165)
• Mechanistic insights into specificity, activity, and regulatory elements of the regulator of G-protein signaling (RGS)-containing Rho-specific guanine nucleotide exchange factors (GEFs) p115, PDZ-RhoGEF (PRG), and leukemia-associated RhoGEF (LARG). (PMID:21454492)
• Thromboxane receptor signaling is required for fibronectin-induced matrix metalloproteinase 9 production by human and murine macrophages and is attenuated by the Arhgef1 molecule. (PMID:22086927)
• Upon beta(2)AR activation, both betaArrestin2 and p115RhoGEF translocate to the plasma membrane, with concomitant activation of RhoA and formation of focal adhesions and stress fibers. (PMID:22500016)
• Activation of p115-RhoGEF requires direct association of Galpha13 and the Dbl homology domain. (PMID:22661716)
• High GEF1 expression is associated with metastasis of pancreatic cancer. (PMID:23070684)
• The action of DOCK7 in vivo may involve the coordinated integration of Cdc42/Rac1 signaling in the context of the membrane recruitment of a DOCK7 guanine nucleotide exchange factor (GEF) complex. (PMID:23718289)
• Modification of p115RhoGEF at Serine(330) regulates its RhoGEF activity. (PMID:23816534)
• The novel role for p115RhoGEF in regulation of epithelial plasticity is dependent on Rho-DRF signaling module. (PMID:24465552)
• Regulated localization is sufficient for hormonal control of regulator of G protein signaling homology Rho guanine nucleotide exchange factors (RH-RhoGEFs). (PMID:24855647)
• contactin-1 displayed the ability to phosphorylate the RhoA activator p115 RhoGEF (PMID:25916117)
• We have reported here for the first time a reduced activity of both Rac1 and Cdc42 in human pheochromocytoma resection as well as tumor-associated expression changes of FARP1, ARHGEF1, and ARHGAP36 (PMID:26911374)
• Data indicate that the crystal structure of PDZ-RhoGEF PDZ domain in complex with the CXC chemokine receptor 2 (CXCR2) C-terminal PDZ binding motif. (PMID:28179147)
• Data suggest that MCP1/CCL2 induces activation/tyrosine phosphorylation of ARHGEF1/p115-RhoGEF and up-regulates RAC1 signaling in vascular smooth muscle cells (VSMCs); ARHGEF1 inhibition suppresses MCP1-induced VSMC migration and proliferation. (ARHGEF1 = Rho guanine nucleotide exchange factor 1; RAC1 = Rac family small GTPase 1; CCL2 = C-C motif chemokine ligand 2) (PMID:28655771)
• High ARHGEF1 expression is associated with asthmatic airway hyper-responsiveness. (PMID:29071730)
• Identification of Rho GEF and RhoA Activation by Pull-Down Assays. (PMID:32808262)
• Integrative multiomics and in silico analysis revealed the role of ARHGEF1 and its screened antagonist in mild and severe COVID-19 patients. (PMID:35037717)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgef1	ENSDARG00000055837
mus_musculus	Arhgef1	ENSMUSG00000040940
rattus_norvegicus	Arhgef1	ENSRNOG00000020130
drosophila_melanogaster	RhoGEF2	FBGN0023172
drosophila_melanogaster	cyst	FBGN0032796
caenorhabditis_elegans		WBGENE00006468
caenorhabditis_elegans	prhg-1	WBGENE00022391

Paralogs (8): PLEKHG6 (ENSG00000008323), ARHGEF18 (ENSG00000104880), ARHGEF2 (ENSG00000116584), ARHGEF11 (ENSG00000132694), ARHGEF3 (ENSG00000163947), NET1 (ENSG00000173848), ARHGEF12 (ENSG00000196914), ARHGEF28 (ENSG00000214944)

Protein

Protein identifiers

Rho guanine nucleotide exchange factor 1 — Q92888 (reviewed: Q92888)

Alternative names: 115 kDa guanine nucleotide exchange factor, Sub1.5

All UniProt accessions (13): Q92888, A0A8V8TMG9, A0A8V8TMH9, A0A8V8TP90, A0A9L9PYI1, M0QXV6, M0QYC1, M0QYS3, M0QZH8, M0QZR4, M0R1K8, M0R2C7, M0R3H5

UniProt curated annotations — full annotation on UniProt →

Function. Seems to play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13) subunits. Acts as a GTPase-activating protein (GAP) for GNA12 and GNA13, and as guanine nucleotide exchange factor (GEF) for RhoA GTPase. Activated G alpha 13/GNA13 stimulates the RhoGEF activity through interaction with the RGS-like domain. This GEF activity is inhibited by binding to activated GNA12. Mediates angiotensin-2-induced RhoA activation. In lymphoid follicles, may trigger activation of GNA13 as part of S1PR2-dependent signaling pathway that leads to inhibition of germinal center (GC) B cell growth and migration outside the GC niche.

Subunit / interactions. Interacts with RHOA, GNA12 and GNA13. Homooligomerizes through the coiled coil region. May interact with CCPG1. Interacts with CTNNAL1.

Subcellular location. Cytoplasm. Membrane.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Phosphorylated by PKCA. Angiotensin-2 induced Tyr-738 phosphorylation is mediated by JAK2.

Disease relevance. Immunodeficiency 62 (IMD62) [MIM:618459] An autosomal recessive, primary immunologic disorder characterized by recurrent severe respiratory tract infections and bronchiectasis, due to antibody deficiency. Affected individuals have an abnormal B cell immunophenotype, with low levels of circulating memory B cells. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RGSL domain, also known as rgRGS domain, is necessary but not sufficient for GAP activity. The DH domain is involved in interaction with CCPG1.

Isoforms (4)

UniProt ID	Names	Canonical?
Q92888-1	1	yes
Q92888-2	2
Q92888-3	3
Q92888-4	4

RefSeq proteins (8): NP_001382929, NP_001382931, NP_001382932, NP_001382933, NP_001382935, NP_004697, NP_945328, NP_945353 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR015212	RGS-like_dom	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036305	RGS_sf	Homologous_superfamily
IPR037887	p115RhoGEF_RGS	Domain
IPR041020	PH_16	Domain
IPR044926	RGS_subdomain_2	Homologous_superfamily

Pfam: PF00621, PF09128, PF17838

UniProt features (77 total): helix 28, strand 12, sequence conflict 10, modified residue 5, domain 3, compositionally biased region 3, splice variant 3, sequence variant 3, turn 3, region of interest 3, mutagenesis site 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
1IAP	X-RAY DIFFRACTION	1.9
3AB3	X-RAY DIFFRACTION	2.4
3P6A	X-RAY DIFFRACTION	2.5
1SHZ	X-RAY DIFFRACTION	2.85
3ODO	X-RAY DIFFRACTION	2.9
3ODW	X-RAY DIFFRACTION	3.2
3ODX	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92888-F1	74.49	0.48

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 (5): 374, 409, 695, 738, 863

Mutagenesis-validated functional residues (2):

Position	Phenotype
487	no effect.
738	lowers the exchange activity.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-194315	Signaling by Rho GTPases
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-73887	Death Receptor Signaling
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 276 (showing top): BIOCARTA_RHO_PATHWAY, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, GCM_MSN, MODULE_45, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GGGTGGRR_PAX4_03, LIAO_METASTASIS, JECHLINGER_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_DN, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, PID_LYSOPHOSPHOLIPID_PATHWAY, FAELT_B_CLL_WITH_VH3_21_UP, MORF_IKBKG

GO Biological Process (4): G protein-coupled receptor signaling pathway (GO:0007186), Rho protein signal transduction (GO:0007266), regulation of small GTPase mediated signal transduction (GO:0051056), Rho-activating G protein-coupled receptor signaling pathway (GO:0160221)

GO Molecular Function (5): G protein-coupled receptor binding (GO:0001664), RNA binding (GO:0003723), guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
RHO GTPase cycle	3
Signal Transduction	3
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Signaling by GPCR	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
small GTPase-mediated signal transduction	2
GTPase regulator activity	2
G protein-coupled receptor activity	1
signal transduction	1
regulation of intracellular signal transduction	1
G protein-coupled receptor signaling pathway	1
signaling receptor binding	1
nucleic acid binding	1
GTP binding	1
GDP binding	1
GTPase activity	1
enzyme activator activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1770 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGEF1	GNA12	Q03113	991
ARHGEF1	GNA13	Q14344	985
ARHGEF1	RHOA	P06749	907
ARHGEF1	MCF2	P10911	827
ARHGEF1	RGS21	Q2M5E4	799
ARHGEF1	RGS8	P57771	795
ARHGEF1	RGS11	O94810	793
ARHGEF1	RGS17	Q9UGC6	788
ARHGEF1	RGS20	O76081	788
ARHGEF1	RGS12	O14924	788
ARHGEF1	RGS6	P49758	788
ARHGEF1	RGS13	O14921	786
ARHGEF1	RGS5	O15539	775
ARHGEF1	RGS10	O43665	775
ARHGEF1	RGS18	Q9NS28	773

IntAct

73 interactions, top by confidence:

A	B	Type	Score
RHOA	ARHGEF11	psi-mi:“MI:0914”(association)	0.900
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
PSMC3	PSMD12	psi-mi:“MI:0914”(association)	0.640
AP2S1	AP2A2	psi-mi:“MI:0914”(association)	0.640
ARHGEF1	espH	psi-mi:“MI:0915”(physical association)	0.600
ARHGEF1	espH	psi-mi:“MI:0403”(colocalization)	0.600
ARHGEF1	TCF4	psi-mi:“MI:0915”(physical association)	0.560
TCF4	ARHGEF1	psi-mi:“MI:0915”(physical association)	0.560
GNA13	ARHGEF1	psi-mi:“MI:0915”(physical association)	0.560
ARHGEF1	GNA13	psi-mi:“MI:0914”(association)	0.560
ARHGEF1	RHOB	psi-mi:“MI:0915”(physical association)	0.550
RHOC	ARHGEF11	psi-mi:“MI:0914”(association)	0.530
ZNRD2	MYO9A	psi-mi:“MI:0914”(association)	0.530
ATP6V0A1	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
ARHGEF1	H3-4	psi-mi:“MI:0915”(physical association)	0.400
DOCK4	ARHGEF1	psi-mi:“MI:0915”(physical association)	0.400
PLEK	ARHGEF1	psi-mi:“MI:0915”(physical association)	0.400
CSNK1E	ARHGEF1	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
ANG	DDX39A	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
DCUN1D1	RGSL1	psi-mi:“MI:0914”(association)	0.350
RHOA	TAX1BP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (175): ARHGEF1 (Two-hybrid), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Co-fractionation), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS)

ESM2 similar proteins: A2AB59, B1AK53, B2DD29, D3YZU1, D3ZG83, O09039, O14976, O54967, O75427, P80192, P98171, Q02779, Q17R13, Q3TBD2, Q3U1V8, Q3UHC7, Q4ACU6, Q4LDD4, Q5DU25, Q5JU85, Q5RB40, Q5RJI5, Q5TCX8, Q5U2X5, Q5VWQ8, Q61097, Q61210, Q66HA1, Q66L42, Q6TLK4, Q6ZUM4, Q80XI6, Q86VW2, Q8IVT5, Q8R0S2, Q8R5F8, Q8R5G7, Q8TDC3, Q8TE68, Q8WWN8

Diamond homologs: A1IGU3, A1IGU4, A4D2P6, A5PKA5, A8MUH7, O14745, O15085, Q0QWG9, Q28619, Q3T0X8, Q3UHD6, Q4R6G4, Q5RCF7, Q5T2W1, Q5ZM14, Q61085, Q61210, Q6ZM86, Q865P3, Q86UT5, Q8K4V4, Q8R4H2, Q8TCX5, Q92888, Q96L92, Q99MJ6, Q9ES67, Q9JIL4, Q9JJ40, Q9NZN5, Q9Z1I6, O94827, Q3KR16, Q66T02, Q6RFZ7, Q8R0J1, B2DCZ9, E9Q394, F1M3G7, P0C6P5

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
JAK2	up-regulates	ARHGEF1	phosphorylation
GNA13	“up-regulates activity”	ARHGEF1	binding
ARHGEF1	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
PRKCA	“up-regulates activity”	ARHGEF1	phosphorylation
GNA13	up-regulates	ARHGEF1	“gtpase-activating protein”
GNA13	up-regulates	ARHGEF1	binding
ARHGEF1	up-regulates	RHOA	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 97 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 PKNs	5	24.0×	5e-04
G alpha (12/13) signalling events	6	12.5×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
Rho protein signal transduction	6	17.7×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	464
Likely benign	416
Benign	31

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
545227	Single allele	Likely pathogenic

SpliceAI

4578 predictions. Top by Δscore:

Variant	Effect	Δscore
19:41888189:CA:C	acceptor_loss	1.0000
19:41888191:GGC:G	acceptor_gain	1.0000
19:41888255:GATTT:G	donor_gain	1.0000
19:41888275:GACA:G	donor_gain	1.0000
19:41888279:G:GG	donor_gain	1.0000
19:41892023:A:AG	acceptor_gain	1.0000
19:41892024:G:GT	acceptor_gain	1.0000
19:41892024:GC:G	acceptor_gain	1.0000
19:41892024:GCT:G	acceptor_gain	1.0000
19:41892024:GCTT:G	acceptor_gain	1.0000
19:41892024:GCTTT:G	acceptor_gain	1.0000
19:41892121:GCG:G	donor_gain	1.0000
19:41892372:TGG:T	donor_loss	1.0000
19:41892374:G:C	donor_loss	1.0000
19:41892374:G:GG	donor_gain	1.0000
19:41892601:A:AG	acceptor_gain	1.0000
19:41892601:A:C	acceptor_loss	1.0000
19:41892601:AGACC:A	acceptor_gain	1.0000
19:41892602:G:GA	acceptor_gain	1.0000
19:41892602:GAC:G	acceptor_gain	1.0000
19:41892602:GACC:G	acceptor_gain	1.0000
19:41892602:GACCG:G	acceptor_gain	1.0000
19:41892845:ATGCA:A	donor_gain	1.0000
19:41892846:TGCA:T	donor_gain	1.0000
19:41892847:GCA:G	donor_gain	1.0000
19:41892847:GCAG:G	donor_gain	1.0000
19:41892848:CA:C	donor_gain	1.0000
19:41892849:AGT:A	donor_loss	1.0000
19:41892850:G:GG	donor_gain	1.0000
19:41892851:T:G	donor_loss	1.0000

AlphaMissense

5916 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:41898512:T:A	W398R	1.000
19:41898512:T:C	W398R	1.000
19:41901890:T:C	L424P	1.000
19:41901923:T:C	L435P	1.000
19:41901932:T:C	L438P	1.000
19:41902811:C:A	R551S	1.000
19:41902815:T:C	L552P	1.000
19:41902854:T:C	L565P	1.000
19:41902861:G:C	K567N	1.000
19:41902861:G:T	K567N	1.000
19:41902862:T:C	Y568H	1.000
19:41902863:A:G	Y568C	1.000
19:41902872:T:C	L571P	1.000
19:41903364:T:C	L599P	1.000
19:41904078:T:C	L654P	1.000
19:41904083:T:A	W656R	1.000
19:41904083:T:C	W656R	1.000
19:41904967:T:A	V727D	1.000
19:41905006:T:C	L740P	1.000
19:41905176:T:A	W751R	1.000
19:41905176:T:C	W751R	1.000
19:41888816:T:C	L59P	0.999
19:41898514:G:C	W398C	0.999
19:41898514:G:T	W398C	0.999
19:41901890:T:A	L424Q	0.999
19:41901899:C:T	T427I	0.999
19:41901902:A:T	E428V	0.999
19:41901903:G:C	E428D	0.999
19:41901903:G:T	E428D	0.999
19:41901908:C:A	A430D	0.999

dbSNP variants (sampled 300 via entrez): RS1000034870 (19:41902682 C>T), RS1000076635 (19:41917743 G>A), RS1000236192 (19:41926648 G>A,C), RS1000282234 (19:41885118 C>T), RS1000501515 (19:41883332 T>C,G), RS1000568600 (19:41925174 C>A,T), RS1000568967 (19:41884833 A>G), RS1000932265 (19:41896380 C>T), RS1001020145 (19:41883700 C>T), RS1001074766 (19:41889470 C>T), RS1001115757 (19:41919329 T>C), RS1001188354 (19:41927692 C>T), RS1001220874 (19:41927983 T>C,G), RS1001489091 (19:41905958 C>T), RS1001596348 (19:41899371 T>A,C)

Disease associations

OMIM: gene MIM:601855 | disease phenotypes: MIM:618459, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 62	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 62	Limited	AR

Mondo (2): immunodeficiency 62 (MONDO:0032763), schizophrenia (MONDO:0005090)

Orphanet (2): Childhood-onset common variable immunodeficiency due to ARHGEF1 deficiency (Orphanet:696942), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

15 total (16 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001973	Autoimmune thrombocytopenia
HP:0002110	Bronchiectasis
HP:0002783	Recurrent lower respiratory tract infections
HP:0002788	Recurrent upper respiratory tract infections
HP:0002850	Decreased circulating total IgM
HP:0003621	Juvenile onset
HP:0004315	Decreased circulating IgG concentration
HP:0005353	Recurrent herpes
HP:0005428	Severe recurrent varicella
HP:0010976	Decreased total B cell count
HP:0030374	Decreased proportion of memory B cells
HP:0030381	Increased transitional B cell proportion
HP:0032139	Reduced isohemagglutinin level
HP:0410295	Complete or near-complete absence of specific antibody response to tetanus vaccine
HP:0100753	Schizophrenia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009849_12	Hallux valgus	6.000000e-07
GCST010703_14	Brain morphology (MOSTest)	1.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4295918 (SINGLE PROTEIN), CHEMBL4523645 (PROTEIN COMPLEX)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.77	Kd	1700	nM	CHEMBL3752910
5.77	ED50	1700	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 13 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149829: Binding affinity to human ARHGEF1 incubated for 45 mins by Kinobead based pull down assay	kd	1.6999	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, affects cotreatment, decreases expression	2
Doxorubicin	decreases expression, increases expression	2
Nickel	increases expression	2
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation, affects cotreatment	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
cupric chloride	increases expression	1
muconaldehyde	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases methylation	1
(+)-JQ1 compound	decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	increases abundance, affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Caffeine	decreases phosphorylation	1
Dexamethasone	affects cotreatment, increases expression	1
Environmental Pollutants	affects expression	1
Furaldehyde	affects cotreatment, decreases expression, affects localization, increases expression	1
Indomethacin	affects cotreatment, increases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4150761	Binding	Inhibition of p115 DHPH22 domain (395 to 766 residues) (unknown origin) interaction with GDP-loaded His-tagged RhoA F25N mutant (1 to 180 residues) assessed as reduction in BODIPY-GTP-GDP exchange at 200 uM pretreated for 30 mins followed b	Natural Inhibitors of the RhoA-p115 Complex from the Bark of Meiogyne baillonii. — J Nat Prod

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2S3	Abcam HEK293T ARHGEF1 KO	Transformed cell line	Female
CVCL_SD37	HAP1 ARHGEF1 (-) 1	Cancer cell line	Male
CVCL_SD38	HAP1 ARHGEF1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety