ARHGEF12

Summary

ARHGEF12 (Rho guanine nucleotide exchange factor 12, HGNC:14193) is a protein-coding gene on chromosome 11q23.3, encoding Rho guanine nucleotide exchange factor 12 (Q9NZN5). Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13.

Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli working through G protein-coupled receptors. The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals. This protein has been observed to form a myeloid/lymphoid fusion partner in acute myeloid leukemia. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23365 — RefSeq curated summary.

At a glance

• GWAS associations: 30
• Clinical variants (ClinVar): 202 total
• Phenotypes (HPO): 1
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• MANE Select transcript: NM_015313

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14193
Approved symbol	ARHGEF12
Name	Rho guanine nucleotide exchange factor 12
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0382, LARG
Ensembl gene	ENSG00000196914
Ensembl biotype	protein_coding
OMIM	604763
Entrez	23365

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 11 retained_intron, 10 protein_coding

ENST00000356641, ENST00000397843, ENST00000525222, ENST00000525960, ENST00000526067, ENST00000528225, ENST00000528681, ENST00000529970, ENST00000530388, ENST00000530747, ENST00000531616, ENST00000532823, ENST00000532993, ENST00000612968, ENST00000884473, ENST00000884474, ENST00000884475, ENST00000884476, ENST00000884477, ENST00000884478, ENST00000884479

RefSeq mRNA: 3 — MANE Select: NM_015313 NM_001198665, NM_001301084, NM_015313

CCDS: CCDS41727, CCDS55794, CCDS76487

Canonical transcript exons

ENST00000397843 — 41 exons

Exon	Start	End
ENSE00001125757	120479960	120480430
ENSE00001364735	120485067	120489937
ENSE00001369958	120484438	120484507
ENSE00001401289	120481260	120481576
ENSE00002172160	120336413	120337275
ENSE00003458749	120421803	120421852
ENSE00003459241	120467194	120467308
ENSE00003464116	120473050	120473127
ENSE00003473609	120407738	120407823
ENSE00003484204	120437308	120437382
ENSE00003492060	120441707	120441817
ENSE00003498840	120449109	120449214
ENSE00003505818	120458080	120458234
ENSE00003509222	120406118	120406141
ENSE00003512400	120447874	120447906
ENSE00003520172	120457118	120457250
ENSE00003524599	120420753	120420851
ENSE00003528593	120475340	120475507
ENSE00003532485	120474560	120474635
ENSE00003539605	120469288	120469388
ENSE00003547032	120431771	120431911
ENSE00003547949	120448234	120448348
ENSE00003549968	120465237	120465362
ENSE00003552236	120446948	120447085
ENSE00003560346	120477447	120477526
ENSE00003571884	120424358	120424415
ENSE00003581706	120460672	120460757
ENSE00003592166	120440129	120440221
ENSE00003596169	120478156	120478389
ENSE00003603079	120476661	120476748
ENSE00003607462	120409394	120409450
ENSE00003611959	120451512	120451724
ENSE00003638185	120459174	120459320
ENSE00003642634	120457721	120457756
ENSE00003644878	120429440	120429517
ENSE00003664728	120477219	120477305
ENSE00003668762	120446403	120446508
ENSE00003678587	120429712	120429831
ENSE00003679124	120428069	120428247
ENSE00003688423	120445422	120445464
ENSE00003690025	120442104	120442202

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 98.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.6117 / max 760.7416, expressed in 1776 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117154	15.9653	1738
117153	3.8015	1537
117160	2.3576	134
117156	2.1630	1179
117155	1.6406	966
117157	0.4602	205
117158	0.4127	148
206477	0.4122	205
117152	0.2260	76
117161	0.1064	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	98.79	gold quality
visceral pleura	UBERON:0002401	98.78	gold quality
heart right ventricle	UBERON:0002080	98.59	gold quality
renal medulla	UBERON:0000362	98.31	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.24	gold quality
parietal pleura	UBERON:0002400	98.20	gold quality
pleura	UBERON:0000977	98.10	gold quality
skin of hip	UBERON:0001554	98.07	gold quality
penis	UBERON:0000989	97.96	gold quality
myocardium	UBERON:0002349	97.96	gold quality
pigmented layer of retina	UBERON:0001782	97.93	gold quality
choroid plexus epithelium	UBERON:0003911	97.84	gold quality
calcaneal tendon	UBERON:0003701	97.79	gold quality
tongue squamous epithelium	UBERON:0006919	97.79	gold quality
palpebral conjunctiva	UBERON:0001812	97.71	gold quality
gingival epithelium	UBERON:0001949	97.69	gold quality
CA1 field of hippocampus	UBERON:0003881	97.69	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.68	gold quality
biceps brachii	UBERON:0001507	97.66	gold quality
hair follicle	UBERON:0002073	97.66	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.66	gold quality
seminal vesicle	UBERON:0000998	97.63	gold quality
upper arm skin	UBERON:0004263	97.61	gold quality
jejunal mucosa	UBERON:0000399	97.52	gold quality
jejunum	UBERON:0002115	97.51	gold quality
left ventricle myocardium	UBERON:0006566	97.44	gold quality
tibia	UBERON:0000979	97.42	gold quality
gingiva	UBERON:0001828	97.33	gold quality
synovial joint	UBERON:0002217	97.31	gold quality
urethra	UBERON:0000057	97.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	27.89
E-HCAD-10	yes	16.25
E-MTAB-8271	yes	14.85
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

188 targeting ARHGEF12, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4725-3P	99.96	69.53	2520

Literature-anchored findings (GeneRIF, showing 31)

• Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation: evidence of a role for focal adhesion kinase (PMID:11799111)
• Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated protein and PDZ-RhoGEF. (PMID:12183458)
• LARG plays a critical role in plexin-B1 signaling to stimulate Rho activation and cytoskeletal reorganization. (PMID:12196628)
• Rho activation through Galpha12 and the regulation of RhoGEFs by heterotrimeric G proteins G1213 is further modulated by tyrosine phosphorylated leukemia-associated RhoGEF. (PMID:12515866)
• 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)
• analysis of LARG RhoA binding and nucleotide exchange structure (PMID:15331592)
• CD44 interaction with LARG and EGFR plays a pivotal role in Rho/Ras co-activation, PLC epsilon-Ca2+ signaling, and Raf/ERK up-regulation required for CaMKII-mediated cytoskeleton function and in head and neck squamous cell carcinoma progression (PMID:16565089)
• Tyr1306Cys substitution in LARG, through its differential activation of RhoA, increases insulin sensitivity in nondiabetic Pima Indians. (PMID:16644711)
• There is no evidence in the Caucasian KORA study that variants of the LARG gene confer susceptibility for type 2 diabetes, insulin sensitivity, or the metabolic syndrome (PMID:17766704)
• Analysis of the (15)N relaxation data using reduced spectral density mapping shows that the apo LARG PDZ is flexible and exhibits internal motions on both picosecond to nanosecond and microsecond to millisecond timescales (PMID:18411422)
• LARG activation is regulated by an induced-fit mechanism through the GAP interface of Galpha(13). (PMID:19074425)
• Moreover, leukemia-associated guanine nucleotide exchange factor (LARG) associates with Unc5B to transduce the RhoA signal. (PMID:19273616)
• mutations in the hydrophobic patch do not have a significant effect on in vitro activity, but abolished the ability of LARG to activate RhoA and to induce stress fiber formation in cultured cells. (PMID:19560536)
• LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast and colorectal cancer (PMID:19734946)
• a novel physical and functional interaction between ABCA1 and PDZ-RhoGEF/LARG, which activates RhoA, resulting in ABCA1 stabilization and cholesterol efflux activity. (PMID:20348106)
• 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)
• The PDZ domain of LARG is required HRH1-mediated activation of the strictly Rho-dependent transcriptional activity of serum response factor and can be mimicked by activated Galpha(q)(Q209L). (PMID:22100544)
• NIS enhanced cell migration and invasion by binding to leukemia-associated RhoA guanine exchange factor (PMID:22962269)
• RhoGEF activity of p210 BCR/ABL directly contributes to transforming activity, and may account for the difference in disease outcome associated with p190 BCR/ABL and p210 BCR/ABL. (PMID:23207522)
• LARG is a novel and temporally distinct Rho Guanine Nucleotide Exchange Factor required for completion of abscission. (PMID:23885121)
• Agonist-induced Ca2+ sensitization in smooth muscle: redundancy of Rho guanine nucleotide exchange factors (RhoGEFs) and response kinetics, a caged compound study. (PMID:24106280)
• Data indicate that ICAM-1 signaling activates leukemia-associated Rho guanine nucleotide exchange factor (LARG), also known as Rho GEF 12 (ARHGEF12). (PMID:24585879)
• TGF-beta regulates LARG and GEF-H1 during epithelial-mesenchymal transition to affect stiffening response to force and cell invasion. (PMID:25143398)
• this study identified a novel association between IOP and ARHGEF12. (PMID:25637523)
• that leukemia-associated Rho guanine-nucleotide exchange factor can be directly phosphorylated by cyclin-dependent kinase 1 (PMID:26483157)
• Two related guanine nucleotide exchange factors (GEFs), PDZ-RhoGEF and leukemia-associated RhoGEF (LARG), use their PDZ domains to bind class B plexins and play critical roles in signaling. (PMID:26627240)
• We studied the function of LARG in murine and human megakaryocytes and platelets with Larg knockout (KO), shRNA-mediated knockdown and small molecule-mediated inhibition. We found that LARG is important for human, but not murine, megakaryocyte maturation. (PMID:27345948)
• Data show that phosphorylation of ribosomal protein S6 kinase 2 (RSK2) at threonine 577 is essential for leukemia-associated RhoGEF (LARG)-dependent Rho GTPase activation. (PMID:29279389)
• ARHGEF12 regulates erythropoiesis and is involved in erythroid regeneration after chemotherapy in acute lymphoblastic leukemia patients. (PMID:31467124)
• ArhGEF12 activates Rap1A and not RhoA in human dermal microvascular endothelial cells to reduce tumor necrosis factor-induced leak. (PMID:35294066)
• Targeting ARHGEF12 promotes neuroblastoma differentiation, MYCN degradation, and reduces tumorigenicity. (PMID:36520365)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgef12a	ENSDARG00000030532
danio_rerio	arhgef12b	ENSDARG00000100913
mus_musculus	Arhgef12	ENSMUSG00000059495
rattus_norvegicus	Arhgef12	ENSRNOG00000008924
drosophila_melanogaster	cyst	FBGN0032796
caenorhabditis_elegans	prhg-1	WBGENE00022391

Paralogs (8): PLEKHG6 (ENSG00000008323), ARHGEF1 (ENSG00000076928), ARHGEF18 (ENSG00000104880), ARHGEF2 (ENSG00000116584), ARHGEF11 (ENSG00000132694), ARHGEF3 (ENSG00000163947), NET1 (ENSG00000173848), ARHGEF28 (ENSG00000214944)

Protein

Protein identifiers

Rho guanine nucleotide exchange factor 12 — Q9NZN5 (reviewed: Q9NZN5)

Alternative names: Leukemia-associated RhoGEF

All UniProt accessions (2): E9PMR6, Q9NZN5

UniProt curated annotations — full annotation on UniProt →

Function. Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13. May play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Promotes endothelial cell and actin stress fiber reorientation in response to mechanotransduction.

Subunit / interactions. Interacts (probably via RGSL domain) with GNA12 and GNA13. Interacts with RHOA. Interacts with PLXNB1. Interacts with PLXNB2. Interacts (via PDZ domain) with IGF1R beta subunit. Interacts with GCSAM. Interacts with PLEKHG4B; the interaction releases PLEKHG4B autoinhibition and results in activation of CDC42.

Subcellular location. Cytoplasm. Membrane.

Tissue specificity. Ubiquitously expressed. Isoform 2 is found in jejunum and testis.

Disease relevance. A chromosomal aberration involving ARHGEF12 may be a cause of acute leukemia. Translocation t(11;11)(q23;23) with KMT2A/MLL1.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NZN5-1	1	yes
Q9NZN5-2	2

RefSeq proteins (3): NP_001185594, NP_001288013, NP_056128* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001331	GDS_CDC24_CS	Conserved_site
IPR001478	PDZ	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR015212	RGS-like_dom	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036305	RGS_sf	Homologous_superfamily
IPR037801	ARHGEF12_PH	Domain
IPR037884	LARG_RGS	Domain
IPR041020	PH_16	Domain
IPR044926	RGS_subdomain_2	Homologous_superfamily

Pfam: PF00595, PF00621, PF09128, PF17838

UniProt features (73 total): helix 21, strand 16, modified residue 12, compositionally biased region 9, domain 4, region of interest 4, initiator methionine 1, chain 1, coiled-coil region 1, site 1, splice variant 1, sequence variant 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1TXD	X-RAY DIFFRACTION	2.13
1X86	X-RAY DIFFRACTION	3.22
2OMJ	SOLUTION NMR
2OS6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZN5-F1	61.20	0.27

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): 308–309 (breakpoint for translocation to form kmt2a/mll1-arhgef12 oncogene)

Post-translational modifications (12): 2, 41, 309, 341, 637, 736, 1288, 1327, 1377, 1457, 1541, 41

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-416572	Sema4D induced cell migration and growth-cone collapse
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-1266738	Developmental Biology
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-373755	Semaphorin interactions
R-HSA-388396	GPCR downstream signalling
R-HSA-400685	Sema4D in semaphorin signaling
R-HSA-422475	Axon guidance
R-HSA-73887	Death Receptor Signaling
R-HSA-9012999	RHO GTPase cycle
R-HSA-9675108	Nervous system development
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 316 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, MYAATNNNNNNNGGC_UNKNOWN, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, TAATAAT_MIR126, YAGI_AML_WITH_INV_16_TRANSLOCATION, PAX4_01, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, TGACCTY_ERR1_Q2, TACAATC_MIR508, GGGTGGRR_PAX4_03, FOXD3_01, AGGCACT_MIR5153P

GO Biological Process (5): 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), intracellular signal transduction (GO:0035556)

GO Molecular Function (4): G protein-coupled receptor binding (GO:0001664), 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), membrane (GO:0016020), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
RHO GTPase cycle	4
Signal Transduction	2
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1
Sema4D in semaphorin signaling	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Axon guidance	1
Signaling by GPCR	1
Semaphorin interactions	1
Nervous system development	1
Signaling by Rho GTPases	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

1754 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGEF12	GNA12	Q03113	997
ARHGEF12	RHOA	P06749	990
ARHGEF12	GNA13	Q14344	970
ARHGEF12	PLXNB1	O43157	965
ARHGEF12	PLXNB2	O15031	927
ARHGEF12	GNAQ	P50148	912
ARHGEF12	CD44	P16070	814
ARHGEF12	GNA11	P29992	794
ARHGEF12	PLXNB3	Q9ULL4	779
ARHGEF12	MCF2	P10911	767
ARHGEF12	CDC42	P21181	698
ARHGEF12	RABIF	P47224	689
ARHGEF12	RHOC	P08134	676
ARHGEF12	ADRA1A	P35348	664
ARHGEF12	SEMA4D	Q92854	664

IntAct

254 interactions, top by confidence:

A	B	Type	Score
RHOA	ARHGEF11	psi-mi:“MI:0914”(association)	0.900
SMARCB1	ARID1A	psi-mi:“MI:0914”(association)	0.860
LDHB	LDHA	psi-mi:“MI:0914”(association)	0.800
ARHGEF12	RHOA	psi-mi:“MI:0407”(direct interaction)	0.770
SH3BP4	GIPC1	psi-mi:“MI:0914”(association)	0.740
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
ARHGEF12	GIPC1	psi-mi:“MI:0914”(association)	0.720
ARHGEF12	GIPC1	psi-mi:“MI:0915”(physical association)	0.720
ARHGEF12	GIPC1	psi-mi:“MI:2364”(proximity)	0.720
MYO6	ARHGEF12	psi-mi:“MI:0403”(colocalization)	0.700
MYO6	GIPC1	psi-mi:“MI:0914”(association)	0.690
RPS6KA3	ROCK2	psi-mi:“MI:0914”(association)	0.640
VAPA	FAM83G	psi-mi:“MI:0914”(association)	0.640
VAPA	PITPNM1	psi-mi:“MI:0914”(association)	0.640
DYDC2	INPPL1	psi-mi:“MI:0914”(association)	0.560
ORF	EIF3F	psi-mi:“MI:0914”(association)	0.560
TRMT61A	ARHGEF11	psi-mi:“MI:0914”(association)	0.530
RHOC	ARHGEF11	psi-mi:“MI:0914”(association)	0.530
MYO6	POTEI	psi-mi:“MI:0914”(association)	0.530
GIPC1	APPL2	psi-mi:“MI:0914”(association)	0.480
ARHGEF12	E6	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (178): ARHGEF12 (Biochemical Activity), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Biochemical Activity), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Affinity Capture-MS), ARHGEF12 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2JUG7, A1L390, E9Q0S6, O08774, O14924, O15085, O43182, O54834, O54960, O60307, O75052, P57095, Q13009, Q3U1V8, Q3U214, Q3UHC7, Q4VAC9, Q5DU25, Q5JU85, Q5RBI7, Q5SXA9, Q5VWQ8, Q60610, Q64512, Q6AX33, Q6DN90, Q6NXJ0, Q6P0Q8, Q6P1I6, Q6ZMN7, Q76G19, Q76LL6, Q76M68, Q7T2V3, Q810W7, Q8CGE9, Q8IX03, Q8R0S2, Q8R4H2, Q8WYP3

Diamond homologs: A0A1D5P556, A0A8C0TYJ0, A4D2P6, A5PKA5, A8MUH7, B7WN72, G5ECY0, O08774, O14745, O14924, O15085, O60879, P31007, P31016, P70175, P70441, P78352, P97879, Q09506, Q0D5P3, Q0QWG9, Q12959, Q13425, Q15599, Q15700, Q28619, Q28C55, Q3T0X8, Q3UHD6, Q4R6G4, Q5PYH5, Q5PYH6, Q5PYH7, Q5RCF7, Q5T2W1, Q5ZM14, Q61085, Q61235, Q62108, Q62696

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
ARHGEF12	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
PTK2	“up-regulates activity”	ARHGEF12	phosphorylation
ARHGEF12	up-regulates	RHOA	“guanine nucleotide exchange factor”
GNA13	“up-regulates activity”	ARHGEF12	binding
GNAQ	“up-regulates activity”	ARHGEF12	binding
GNA12	“up-regulates activity”	ARHGEF12	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 198 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
Sema4D induced cell migration and growth-cone collapse	5	19.7×	3e-04
Tight junction interactions	6	15.2×	2e-04
Degradation of CDH1	10	13.6×	2e-06
Defective CFTR causes cystic fibrosis	8	12.1×	6e-05
Hh mutants are degraded by ERAD	7	11.7×	2e-04
Regulation of activated PAK-2p34 by proteasome mediated degradation	6	11.5×	5e-04
SCF-beta-TrCP mediated degradation of Emi1	7	11.5×	2e-04
Regulation of ornithine decarboxylase (ODC)	6	11.2×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
calcium-independent cell-cell adhesion	5	22.1×	8e-04
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	5	18.5×	1e-03
positive regulation of protein targeting to membrane	5	15.4×	2e-03
bicellular tight junction assembly	6	10.9×	2e-03
substantia nigra development	5	10.1×	8e-03
axonogenesis	7	6.2×	8e-03
cell-cell adhesion	10	5.6×	2e-03
cell migration	14	4.7×	8e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — BRCA, CCRCC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	146
Likely benign	9
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

6569 predictions. Top by Δscore:

Variant	Effect	Δscore
11:120406110:T:A	acceptor_gain	1.0000
11:120406139:AAGGT:A	donor_loss	1.0000
11:120406142:GT:G	donor_loss	1.0000
11:120406143:T:A	donor_loss	1.0000
11:120407731:A:AG	acceptor_gain	1.0000
11:120407733:TTTAG:T	acceptor_loss	1.0000
11:120407734:TTAGG:T	acceptor_loss	1.0000
11:120407736:A:AG	acceptor_gain	1.0000
11:120407736:A:T	acceptor_loss	1.0000
11:120407736:AG:A	acceptor_gain	1.0000
11:120407737:G:GT	acceptor_gain	1.0000
11:120407737:GG:G	acceptor_gain	1.0000
11:120407737:GGC:G	acceptor_gain	1.0000
11:120407737:GGCAT:G	acceptor_gain	1.0000
11:120407819:CACAG:C	donor_loss	1.0000
11:120407820:ACAGG:A	donor_loss	1.0000
11:120407822:AGGT:A	donor_loss	1.0000
11:120407823:GGTAA:G	donor_loss	1.0000
11:120407824:G:GA	donor_loss	1.0000
11:120407825:T:G	donor_loss	1.0000
11:120409932:A:AG	acceptor_gain	1.0000
11:120420733:ACACT:A	acceptor_gain	1.0000
11:120420735:ACT:A	acceptor_gain	1.0000
11:120420735:ACTGT:A	acceptor_gain	1.0000
11:120420848:G:GT	donor_gain	1.0000
11:120424354:A:AG	acceptor_gain	1.0000
11:120424356:A:AG	acceptor_gain	1.0000
11:120424356:AG:A	acceptor_gain	1.0000
11:120424356:AGGT:A	acceptor_gain	1.0000
11:120424357:G:A	acceptor_loss	1.0000

AlphaMissense

10139 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:120420764:C:A	R71S	1.000
11:120420765:G:C	R71P	1.000
11:120420767:T:C	C72R	1.000
11:120420769:C:G	C72W	1.000
11:120420777:T:A	I75N	1.000
11:120420795:G:A	G81E	1.000
11:120420797:T:C	F82L	1.000
11:120420799:T:A	F82L	1.000
11:120420799:T:G	F82L	1.000
11:120420800:G:A	G83R	1.000
11:120420800:G:C	G83R	1.000
11:120420800:G:T	G83W	1.000
11:120420801:G:A	G83E	1.000
11:120420804:T:A	L84Q	1.000
11:120420804:T:C	L84P	1.000
11:120420810:T:A	V86D	1.000
11:120420815:G:A	G88R	1.000
11:120420815:G:C	G88R	1.000
11:120420816:G:A	G88E	1.000
11:120420816:G:T	G88V	1.000
11:120420825:C:A	P91Q	1.000
11:120420828:T:A	V92D	1.000
11:120420834:T:A	V94E	1.000
11:120420843:T:A	V97D	1.000
11:120421812:C:A	A103D	1.000
11:120421827:T:A	V108E	1.000
11:120421836:G:T	G111V	1.000
11:120421838:G:C	D112H	1.000
11:120421839:A:C	D112A	1.000
11:120421839:A:G	D112G	1.000

dbSNP variants (sampled 300 via entrez): RS1000019660 (11:120457412 T>G), RS1000027167 (11:120487635 A>G), RS1000030358 (11:120337660 C>T), RS1000033652 (11:120388143 T>C), RS1000037186 (11:120346842 A>C,G), RS1000101427 (11:120427238 T>G), RS1000121692 (11:120338024 G>T), RS1000130289 (11:120406026 C>A), RS1000135505 (11:120360419 G>A,T), RS1000144184 (11:120375153 A>C,G), RS1000166383 (11:120484796 G>A,C), RS1000167756 (11:120344290 A>C), RS1000192003 (11:120350539 A>G), RS1000207478 (11:120487683 C>T), RS1000226804 (11:120470405 C>T)

Disease associations

OMIM: gene MIM:604763 | disease phenotypes: MIM:309800

GenCC curated gene-disease

Mondo (3): breast ductal adenocarcinoma (MONDO:0005590), glaucoma (MONDO:0005041), syndromic microphthalmia (MONDO:0016073)

Orphanet (1): Syndromic microphthalmia-anophthalmia-coloboma (Orphanet:202948)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000501	Glaucoma

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST002582_5	Glaucoma (primary open-angle)	8.000000e-06
GCST002767_28	Intraocular pressure	6.000000e-08
GCST002767_3	Intraocular pressure	6.000000e-07
GCST003657_9	Attention deficit hyperactivity disorder symptom score	9.000000e-06
GCST004074_17	Intraocular pressure	2.000000e-09
GCST005170_16	Intraocular pressure	1.000000e-21
GCST005170_41	Intraocular pressure	6.000000e-15
GCST005194_79	Coronary artery disease	4.000000e-06
GCST005580_149	Intraocular pressure	6.000000e-28
GCST005580_207	Intraocular pressure	5.000000e-25
GCST006065_28	Glaucoma (primary open-angle)	1.000000e-11
GCST006394_92	Intraocular pressure	4.000000e-23
GCST006395_19	Glaucoma	2.000000e-12
GCST006395_41	Glaucoma	2.000000e-11
GCST006412_76	Intraocular pressure	3.000000e-29
GCST008839_68	Height	4.000000e-18
GCST009413_10	Intraocular pressure	3.000000e-10
GCST009722_2	Glaucoma (multi-trait analysis)	1.000000e-21
GCST009725_12	Intraocular pressure	7.000000e-23
GCST009726_36	Glaucoma	1.000000e-07
GCST011438_28	Glaucoma (primary open-angle)	3.000000e-13
GCST011439_15	Glaucoma (primary open-angle)	1.000000e-11
GCST011441_11	Glaucoma (high intraocular pressure)	1.000000e-09
GCST90000025_175	Appendicular lean mass	1.000000e-19
GCST90002393_447	Monocyte count	4.000000e-10
GCST90002400_481	Plateletcrit	7.000000e-20
GCST90002402_397	Platelet count	2.000000e-17
GCST90002407_341	White blood cell count	9.000000e-11
GCST90011766_18	Glaucoma (primary open-angle)	4.000000e-19
GCST90011770_58	Glaucoma (primary open-angle)	1.000000e-24

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0007860	ADHD symptom measurement
EFO:0004980	appendicular lean mass
EFO:0005091	monocyte count
EFO:0007985	platelet crit
EFO:0004309	platelet count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D005901	Glaucoma	C11.525.381

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4523477 (SINGLE PROTEIN), CHEMBL4523647 (PROTEIN COMPLEX)

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

ChEMBL bioactivities

7 potent at pChembl≥5 of 7 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.19	Kd	65	nM	CHEMBL485210
7.10	Kd	79	nM	CHEMBL485210
6.33	Kd	472	nM	CHEMBL485210
6.00	IC50	1000	nM	CHEMBL485210
5.67	Kd	2121	nM	CHEMBL485210
5.30	IC50	5000	nM	CHEMBL485210
5.00	IC50	1e+04	nM	CHEMBL4463605

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases methylation, affects cotreatment	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
coumarin	affects phosphorylation	1
pentanal	decreases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
Irinotecan	decreases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Fluvastatin	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	increases response to substance	1
Caffeine	affects phosphorylation	1
Carbamazepine	affects expression	1
Hydralazine	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lead	affects splicing	1
Nickel	decreases expression	1
Smoke	increases abundance, increases expression	1
Thimerosal	increases expression	1
Thiram	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
CHEMBL4419667	Binding	Inhibition of human LARG (765 to 1138 residues) RhoGEF-catalyzed guanine nucleotide-exchange reaction of human full length RhoA (1 to 193 residues) by measuring inhibition of TR-GTP association to RhoA by BODIPY-Texas Red(TR)-GTP nucleotide	Small-molecule inhibitors targeting g-protein-coupled rho guanine nucleotide exchange factors

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00061503	PHASE4	COMPLETED	Mechanism of Action of TRAVATAN 0.004% in Subjects With Glaucoma or Ocular Hypertension
NCT00143208	PHASE4	COMPLETED	Evaluation Of Intraocular Pressure Lowering-Effect Of Xalacom In Patients With Poag Or Oh.
NCT00224289	PHASE4	COMPLETED	Effect of Age on Latanoprost 0.005% in Patients With Glaucoma
NCT00273221	PHASE4	UNKNOWN	Combined Phacotube vs Phacotrabeculectomy:A Randomized Controlled Trial
NCT00329095	PHASE4	COMPLETED	An Evaluation of Use of Topical Ocular Hypotensive Medication by Compliance
NCT00345046	PHASE4	COMPLETED	A Comparison of Three Different Formulations of Prednisolone Acetate 1%
NCT00346489	PHASE4	COMPLETED	Outcomes of Intraoperative 5-Fluorouracil Versus Mitomycin C
NCT00347035	PHASE4	TERMINATED	INFLUENCE OF TOPICAL INDOMETHACIN ON HYPOTHENSIVE EFFECT OF BRIMONIDINE
NCT00347802	PHASE4	COMPLETED	Diurnal Curves With Bimatoprost 0.03% Versus Travoprost 0.004%
NCT00347841	PHASE4	COMPLETED	Efficacy of Bimatoprost 0.03% in Patients Who Are Low-Responders to Latanoprost
NCT00348023	PHASE4	COMPLETED	Bimatoprost Monotherapy vs. Dual Therapy With Travoprost and Timolol in Patients With Glaucoma and Ocular Hypertension
NCT00348062	PHASE4	COMPLETED	A Multicenter Evaluation of Methods to Reduce Hyperemia Associated With Bimatoprost Therapy for Glaucoma or Ocular Hypertension
NCT00348400	PHASE4	COMPLETED	Brimonidine Purite 0.15% Versus Dorzolamide 2% Used as Adjunctive Therapy to Latanoprost
NCT00351429	PHASE4	COMPLETED	Study of PGA Suture in Ophthalmology
NCT00376974	PHASE4	UNKNOWN	The Effect of Education on Patient Compliance
NCT00379834	PHASE4	COMPLETED	12-Month Stability of Diurnal IOP Control on Cosopt
NCT00382226	PHASE4	COMPLETED	IOP-Lowering Efficacy of Brinzolamide 1.0% Added to Travoprost 0.004%/Timolol 0.5% Fixed Combination as Adjunctive Therapy
NCT00404729	PHASE4	COMPLETED	Neural Conduction Along the Visual Pathways After Oral Treatment With Citicoline in Patients With Optic Nerve Diseases
NCT00440011	PHASE4	COMPLETED	Bimatoprost 0.03% Versus Travoprost 0.004% in Patients Currently on Latanoprost 0.005%
NCT00440141	PHASE4	COMPLETED	Brimonidine 0.1% Versus Brinzolamide 1% as Adjunctive Therapy to Latanoprost 0.005%
NCT00442312	PHASE4	UNKNOWN	Combigan Ophthalmic Solution(Brimonidine 0.2% and Timolol 0.5%)With Latanoprost Compared With Latanoprost Monotherapy
NCT00444184	PHASE4	COMPLETED	24-hour Intraocular Pressure Control With Travoprost/Timolol Fixed Combination Versus Travoprost
NCT00444665	PHASE4	COMPLETED	Examining The Efficacy, Safety And Improved Tolerability Of Travoprost BAK Free Ophthalmic Solution (Travatan-Z) Compared To Prior Prostaglandin Therapy
NCT00449098	PHASE4	UNKNOWN	Ologen (OculusGen)-Glaucoma MMC Control Trial in India
NCT00466479	PHASE4	COMPLETED	Brimonidine vs ALTP in Progressing Human Glaucoma
NCT00468429	PHASE4	UNKNOWN	Subconjunctival Bevacizumab to Prevent Bleb Failure After Glaucoma Filtration Surgery
NCT00468988	PHASE4	COMPLETED	Short Term Comparative Study of Xalatan With Benzalkonium Chloride vs. Travatan Z Without Benzalkonium Chloride in Healthy Volunteers
NCT00471380	PHASE4	COMPLETED	A Phase IV Study of Travoprost + Brinzolamide to Treat Glaucoma or Ocular Hypertension
NCT00485238	PHASE4	UNKNOWN	ALPI vs Medical Therapy Effects on Optic Nerve Structure & Function
NCT00486486	PHASE4	COMPLETED	24-hour Intraocular Pressure (IOP) Control With the Bimatoprost/Timolol Fixed Combination
NCT00519753	PHASE4	COMPLETED	Success of Transitioning Uncontrolled Glaucoma Patients From Prior Mono or Adjunctive Therapy to DuoTrav
NCT00541242	PHASE4	COMPLETED	Safety and Efficacy of Bimatoprost Compared With Latanoprost in Patients With Glaucoma or Ocular Hypertension
NCT00557232	PHASE4	COMPLETED	Intraocular Bevacizumab (Avastin) for Rubeosis Iridis
NCT00597181	PHASE4	TERMINATED	A Clinical Study Comparing the Inflammatory Response of the Ex-Press Mini Shunt to Trabeculectomy
NCT00607685	PHASE4	COMPLETED	5FU vs 5FU With Viscoelastic Formulation for the Prevention of Scarring Post-trabeculectomy
NCT00626067	PHASE4	COMPLETED	Study of Patient Use and Perception of the Travatan Dosing Aid
NCT00666237	PHASE4	COMPLETED	Primary Tube Versus Trabeculectomy Study
NCT00698438	PHASE4	COMPLETED	Comparison Of Trabeculectomy Versus The Ex-PRESS Miniature Glaucoma Device In The Same Patient: A Prospective Randomized Study
NCT00705757	PHASE4	COMPLETED	The Effects of Xalatan, Travatan and Lumigan on Skin Pigmentation Near the Eye
NCT00708422	PHASE4	COMPLETED	Effects of Travatan Z and Xalatan on Ocular Surface Health