ARHGEF4

Summary

ARHGEF4 (Rho guanine nucleotide exchange factor 4, HGNC:684) is a protein-coding gene on chromosome 2q21.1, encoding Rho guanine nucleotide exchange factor 4 (Q9NR80). Acts as a guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases.

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

Source: NCBI Gene 50649 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 153 total
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001367493

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:684
Approved symbol	ARHGEF4
Name	Rho guanine nucleotide exchange factor 4
Location	2q21.1
Locus type	gene with protein product
Status	Approved
Aliases	STM6, KIAA1112, ASEF, ASEF1
Ensembl gene	ENSG00000136002
Ensembl biotype	protein_coding
OMIM	605216
Entrez	50649

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000326016, ENST00000355771, ENST00000392953, ENST00000409303, ENST00000409359, ENST00000428230, ENST00000438985, ENST00000490728, ENST00000525092, ENST00000526381, ENST00000527365, ENST00000528247, ENST00000532720, ENST00000611048, ENST00000636987, ENST00000918335, ENST00000918336, ENST00000918337, ENST00000918338

RefSeq mRNA: 8 — MANE Select: NM_001367493 NM_001367493, NM_001375900, NM_001375901, NM_001375902, NM_001375903, NM_001375904, NM_001395416, NM_015320

CCDS: CCDS2165, CCDS92866

Canonical transcript exons

ENST00000409359 — 14 exons

Exon	Start	End
ENSE00000921660	131041230	131041462
ENSE00001070783	131027945	131028084
ENSE00001173924	130946509	130946635
ENSE00002161590	130913986	130917498
ENSE00002195896	130836914	130836992
ENSE00003488757	131038853	131039032
ENSE00003502468	131043452	131043583
ENSE00003559807	131044299	131044542
ENSE00003569455	131045369	131045446
ENSE00003570415	130930952	130931257
ENSE00003629087	131040016	131040192
ENSE00003642273	131040261	131040440
ENSE00003662061	131041815	131041944
ENSE00003901946	131046038	131047253

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 98.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.7129 / max 189.6088, expressed in 985 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22537	3.1351	693
22524	2.0593	465
22523	0.9525	398
22531	0.6635	119
22525	0.2932	143
22535	0.2352	95
22536	0.1594	73
22533	0.1206	73
22534	0.0510	29
22532	0.0431	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	98.26	gold quality
nucleus accumbens	UBERON:0001882	98.08	gold quality
prefrontal cortex	UBERON:0000451	97.67	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.53	gold quality
cingulate cortex	UBERON:0003027	97.44	gold quality
anterior cingulate cortex	UBERON:0009835	97.42	gold quality
amygdala	UBERON:0001876	97.30	gold quality
putamen	UBERON:0001874	97.28	gold quality
caudate nucleus	UBERON:0001873	97.20	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.75	gold quality
Brodmann (1909) area 10	UBERON:0013541	96.49	gold quality
frontal cortex	UBERON:0001870	96.44	gold quality
neocortex	UBERON:0001950	96.17	gold quality
lower esophagus mucosa	UBERON:0035834	96.09	gold quality
middle frontal gyrus	UBERON:0002702	96.08	gold quality
telencephalon	UBERON:0001893	95.88	gold quality
Ammon’s horn	UBERON:0001954	95.61	gold quality
forebrain	UBERON:0001890	95.57	gold quality
cerebral cortex	UBERON:0000956	95.55	gold quality
lateral globus pallidus	UBERON:0002476	95.43	gold quality
frontal pole	UBERON:0002795	95.37	gold quality
hypothalamus	UBERON:0001898	95.35	gold quality
skin of abdomen	UBERON:0001416	95.08	gold quality
temporal lobe	UBERON:0001871	94.89	gold quality
skin of leg	UBERON:0001511	94.73	gold quality
brain	UBERON:0000955	94.65	gold quality
central nervous system	UBERON:0001017	94.61	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.98	gold quality
ventral tegmental area	UBERON:0002691	93.78	gold quality
superior vestibular nucleus	UBERON:0007227	93.72	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	1268.09
E-MTAB-6386	no	3.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 13)

• Positive role of Tyr94 phosphorylation in EGF-induced Asef activation following the activation of Rac1. (PMID:18653540)
• Asef and APC function downstream of HGF and PI3-kinase, and play critical roles in growth factor-mediated regulation of cell morphology and migration (PMID:19525225)
• Forced expression of Asef in vitro induced and maintained proliferation of haemaopoietic progenitor cells and co-operated with TEL-AML1 greatly to enhance proliferation and haemopoietic colony size (PMID:19628279)
• structures thus elucidate the molecular mechanism of Asef recognition by APC (PMID:21788986)
• Expression of ARHGEF4 (Rho guanine nucleotide exchange factor 4) is restricted to the brain and may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function (PMID:22543972)
• Expression of Asef was associated with lower estimated glomerular filtration rate in kidney disease. (PMID:23941980)
• These data demonstrate, that in addition to microtubule-independent Tiam1 activation, HGF engages additional microtubule- and APC-dependent pathway of Asef activation. (PMID:25101856)
• these results demonstrate potent anti-inflammatory effects by HGF and delineate a key role of Asef in the mediation of the HGF barrier protective and anti-inflammatory effects. (PMID:25539852)
• Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumor (PMID:26929985)
• Our results indicate a possible contribution of CNVs in LEPR, NEGR1, ARHGEF4, and CPXCR1 and the intergenic regions 12q15c, 15q21.1a, and 22q11.21d to the development of obesity, particularly abdominal obesity in Mexican children. (PMID:28428959)
• The armadillo repeats in full-length APC interact with the APC residues 1362 to 1540 (APC-2,3 repeats), and this interaction competes off and inhibits Asef. Deletion of APC-2,3 repeats permits Asef interactions leading to downstream signaling events, including the induction of Golgi fragmentation through the activation of the Asef-ROCK-MLC2. (PMID:29866653)
• Evaluation of an immunohistochemical staining of 102 resected pancreatic cancer samples demonstrated that high ARHGEF4 expression was correlated with an independent predictor of worse overall survival. ARHGEF4 induces the formation of cell protrusions by increasing phosphorylated ERK1/2 and GSK-3alpha/beta, resulting in an increase in motility and invasiveness in pancreatic ductal adenocarcinoma cells. (PMID:30226582)
• Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors. (PMID:33670371)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Rho guanine nucleotide exchange factor 4 — Q9NR80 (reviewed: Q9NR80)

Alternative names: APC-stimulated guanine nucleotide exchange factor 1

All UniProt accessions (9): A0A087X0P1, A0A0C4DFY6, A0A1B0GW00, A4QPB6, Q9NR80, E7EV07, E9PEM0, H0Y451, H0YCT6

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases. Binding of APC may activate RAC1 GEF activity. The APC-ARHGEF4 complex seems to be involved in cell migration as well as in E-cadherin-mediated cell-cell adhesion. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression.

Subunit / interactions. Isoform 3 interacts with RHOA and RAC1, and (via ABR domain) with APC. Found in a complex consisting of ARHGEF4, APC and CTNNB1.

Subcellular location. Cytoplasm. Cell projection. Ruffle membrane.

Tissue specificity. Expressed at high levels in the brain, skeletal muscle and testis and at low levels in the kidney, lung, small intestine, ovary and prostate. Expression is aberrantly enhanced in most colorectal tumors.

Domain organisation. In an autoinhibited form the SH3 domain binds intramolecularly to the DH domain, thus blocking the Rac-binding site.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NR80-1	1	yes
Q9NR80-3	3
Q9NR80-4	4

RefSeq proteins (8): NP_001354422, NP_001362829, NP_001362830, NP_001362831, NP_001362832, NP_001362833, NP_001382345, NP_056135 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001331	GDS_CDC24_CS	Conserved_site
IPR001452	SH3_domain	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR055251	SOS1_NGEF_PH	Domain

Pfam: PF00018, PF00621, PF22697

UniProt features (48 total): strand 16, helix 15, turn 4, domain 3, sequence variant 3, region of interest 3, splice variant 3, chain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2PZ1	X-RAY DIFFRACTION	2.25
3NMX	X-RAY DIFFRACTION	2.3
2DX1	X-RAY DIFFRACTION	2.36
3NMZ	X-RAY DIFFRACTION	3.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NR80-F1	70.45	0.41

Function

Pathways and Gene Ontology

Reactome pathways

15 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-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9958810	SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)
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: 159 (showing top): JAEGER_METASTASIS_DN, AAGCCAT_MIR135A_MIR135B, YANG_BREAST_CANCER_ESR1_LASER_DN, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, GOCC_RUFFLE, MODULE_66, PU1_Q6, GOBP_LAMELLIPODIUM_ORGANIZATION, RYTTCCTG_ETS2_B, ELK1_01, GOBP_CELL_PROJECTION_ORGANIZATION, RGAGGAARY_PU1_Q6, MODULE_11, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION

GO Biological Process (4): lamellipodium assembly (GO:0030032), intracellular signal transduction (GO:0035556), filopodium assembly (GO:0046847), regulation of small GTPase mediated signal transduction (GO:0051056)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), protein domain specific binding (GO:0019904), protein binding (GO:0005515)

GO Cellular Component (6): cytosol (GO:0005829), ruffle membrane (GO:0032587), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
RHO GTPase cycle	3
Signal Transduction	3
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1
Activation of STAT3 by cadherin engagement	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	4
plasma membrane bounded cell projection assembly	2
intracellular anatomical structure	2
lamellipodium organization	1
signal transduction	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
protein binding	1
binding	1
cytoplasm	1
ruffle	1
cell projection membrane	1
leading edge membrane	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1357 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGEF4	APC	P25054	868
ARHGEF4	CDC42	P21181	805
ARHGEF4	IQGAP1	P46940	728
ARHGEF4	KIFAP3	Q92845	697
ARHGEF4	RABIF	P47224	608
ARHGEF4	RHOA	P06749	598
ARHGEF4	AXIN1	O15169	563
ARHGEF4	CTNNB1	P35222	552
ARHGEF4	ARHGEF2	Q92974	519
ARHGEF4	CDH1	P12830	503
ARHGEF4	CLIP1	P30622	502
ARHGEF4	PLEK	P08567	492
ARHGEF4	AMER3	Q8N944	488
ARHGEF4	ARHGAP17	Q68EM7	441
ARHGEF4	GSK3B	P49841	434

IntAct

32 interactions, top by confidence:

A	B	Type	Score
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
HSF2BP	ARHGEF4	psi-mi:“MI:0915”(physical association)	0.560
ADAM10	ARHGEF4	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF4	TMCC1	psi-mi:“MI:0915”(physical association)	0.400
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
ANKRD13A	MLF1	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
ARHGEF4	BPGM	psi-mi:“MI:0914”(association)	0.350
INF2	PIPSL	psi-mi:“MI:0914”(association)	0.350
D2HGDH	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
SULT1C4	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
CIAO2A		psi-mi:“MI:0914”(association)	0.350
F12		psi-mi:“MI:0914”(association)	0.350
DHDH	ZNF185	psi-mi:“MI:0914”(association)	0.350
ASB14	TOMM40	psi-mi:“MI:0914”(association)	0.350
ANKRD13A	HLA-DPB1	psi-mi:“MI:0914”(association)	0.350
NEDD8	PRPF3	psi-mi:“MI:0914”(association)	0.350
YWHAB	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAE	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAH	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAQ	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAZ	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	E2F8	psi-mi:“MI:2364”(proximity)	0.270
CLU	ARHGEF4	psi-mi:“MI:0915”(physical association)	0.000
DISC1	ARHGEF4	psi-mi:“MI:0915”(physical association)	0.000
EXOC1	ARHGEF4	psi-mi:“MI:0915”(physical association)	0.000
ARHGEF4	HSF2BP	psi-mi:“MI:0915”(physical association)	0.000
HLA-B	ARHGEF4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (71): ARHGEF4 (Affinity Capture-RNA), ARHGEF4 (Affinity Capture-RNA), ARHGEF4 (Affinity Capture-RNA), ARHGEF4 (Affinity Capture-RNA), HSF2BP (Two-hybrid), TMCC1 (Proximity Label-MS), ARHGEF4 (FRET), ARHGEF4 (FRET), KNOP1 (Affinity Capture-MS), EBNA1BP2 (Affinity Capture-MS), EIF6 (Affinity Capture-MS), FUBP3 (Affinity Capture-MS), MLF2 (Affinity Capture-MS), NUP35 (Affinity Capture-MS), RBM22 (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: A0JNJ1, A1CEK6, A1DFN5, A2QW93, A4RF61, A6QLK6, A7A261, F1LRS8, O35179, O35964, O43307, O74749, O75791, O75886, O88811, O89100, O93436, P02549, P07751, P09215, P09216, P10830, P13395, P16054, P16086, P16546, P23298, P24723, P28867, P29355, P32793, P34885, P38753, P43603, P53281, P62993, P62994, P70297, P87379, P97306

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SRC	up-regulates	ARHGEF4	phosphorylation
ARHGEF4	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
ARHGEF4	“up-regulates activity”	CDC42	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 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
Activation of BAD and translocation to mitochondria	6	190.3×	3e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	167.9×	3e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	167.9×	3e-11
Activation of BH3-only proteins	6	124.1×	2e-10
RHO GTPases activate PKNs	7	92.5×	3e-11
Intrinsic Pathway for Apoptosis	6	73.2×	4e-09
Translocation of SLC2A4 (GLUT4) to the plasma membrane	8	51.4×	6e-11
SARS-CoV-1-host interactions	6	43.9×	9e-08

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	57.2×	4e-06
intracellular protein localization	7	22.9×	4e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	107
Likely benign	17
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

3334 predictions. Top by Δscore:

Variant	Effect	Δscore
2:130931256:AGG:A	donor_loss	1.0000
2:130931258:GTA:G	donor_loss	1.0000
2:130946507:A:AG	acceptor_gain	1.0000
2:130946508:G:GA	acceptor_gain	1.0000
2:130946508:GT:G	acceptor_gain	1.0000
2:131038977:G:GA	donor_gain	1.0000
2:131038979:T:TA	donor_gain	1.0000
2:131038980:G:GA	donor_gain	1.0000
2:131040015:GCTGA:G	acceptor_gain	1.0000
2:131040417:C:G	donor_gain	1.0000
2:131040437:GCAT:G	donor_gain	1.0000
2:131040441:G:GG	donor_gain	1.0000
2:131041228:A:AG	acceptor_gain	1.0000
2:131041229:G:GG	acceptor_gain	1.0000
2:131041229:GCAA:G	acceptor_gain	1.0000
2:131041396:TGCAG:T	donor_gain	1.0000
2:131041409:C:T	donor_gain	1.0000
2:131041460:CAGGT:C	donor_loss	1.0000
2:131041461:AGGT:A	donor_loss	1.0000
2:131041462:GGTA:G	donor_loss	1.0000
2:131041463:GT:G	donor_loss	1.0000
2:131041464:T:A	donor_loss	1.0000
2:131041812:CA:C	acceptor_loss	1.0000
2:131041936:G:GT	donor_gain	1.0000
2:131041942:G:GT	donor_gain	1.0000
2:131041942:G:T	donor_gain	1.0000
2:131041943:AGG:A	donor_loss	1.0000
2:131041945:GTG:G	donor_loss	1.0000
2:131044466:G:GT	donor_gain	1.0000
2:131045367:A:AG	acceptor_gain	1.0000

AlphaMissense

12269 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:131038881:C:A	A199D	1.000
2:131038976:T:A	W231R	1.000
2:131038976:T:C	W231R	1.000
2:131038979:T:A	W232R	1.000
2:131038979:T:C	W232R	1.000
2:131039013:T:C	F243S	1.000
2:131039028:T:A	V248D	1.000
2:131040176:T:C	L303P	1.000
2:131040298:T:C	F321S	1.000
2:131041384:T:C	L420P	1.000
2:131041400:G:C	Q425H	1.000
2:131041400:G:T	Q425H	1.000
2:131041414:A:G	Y430C	1.000
2:131041420:T:C	L432P	1.000
2:131041426:T:C	L434P	1.000
2:131041435:T:C	L437P	1.000
2:131038887:C:A	A201E	0.999
2:131038892:T:A	W203R	0.999
2:131038892:T:C	W203R	0.999
2:131038923:T:C	L213P	0.999
2:131038929:T:C	F215S	0.999
2:131038947:T:A	I221N	0.999
2:131038978:G:C	W231C	0.999
2:131038978:G:T	W231C	0.999
2:131038985:G:C	G234R	0.999
2:131038986:G:A	G234D	0.999
2:131039009:T:A	W242R	0.999
2:131039009:T:C	W242R	0.999
2:131039024:T:C	F247L	0.999
2:131039026:C:A	F247L	0.999

dbSNP variants (sampled 300 via entrez): RS1000028610 (2:131005184 C>G,T), RS1000031829 (2:130837099 C>A,G,T), RS1000033115 (2:130919462 C>T), RS1000034195 (2:130846034 T>C), RS1000046408 (2:130895890 T>C), RS1000047149 (2:131009955 TTTTTG>T,TTTTTGTTTTG,TTTTTGTTTTGTTTTG,TTTTTGTTTTGTTTTGTTTTG), RS1000050582 (2:130991602 G>C), RS1000070238 (2:130877256 A>G,T), RS1000085111 (2:130919075 T>G), RS1000098229 (2:130896206 C>T), RS1000098300 (2:130922095 C>T), RS1000106233 (2:130927081 C>T), RS1000136786 (2:130966678 G>A), RS1000144155 (2:130877227 C>A), RS1000146209 (2:131004969 T>C)

Disease associations

OMIM: gene MIM:605216 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003058_3	Progression free survival in metastatic colorectal cancer (CAPOX-B vs CAPOX-B plus cetuximab)	6.000000e-06
GCST009304_12	Degraded stimulus continuous performance test score	4.000000e-06
GCST011986_1	Congenital left-sided heart lesions	4.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004920	progression free survival
EFO:0007682	response to cetuximab
EFO:0007683	response to CAPOX-B
EFO:1001480	metastatic colorectal cancer
EFO:0007636	attention function measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296093 (PROTEIN COMPLEX)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4377367	ARHGEF4		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, decreases methylation	6
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
trichostatin A	affects cotreatment, decreases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Lead	affects expression, affects methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
manganese chloride	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
belinostat	decreases expression	1
ormosil	affects binding, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
MRK 003	increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	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
CHEMBL4151974	Binding	Inhibition of Flag-APC (303 to 876 residues) (unknown origin) /HA-Asef (170 to 632 residues) (unknown origin) interaction expressed in HEK293T cell lysates incubated for 2 hrs by coimmunoprecipitation assay	Rational Design and Structure Validation of a Novel Peptide Inhibitor of the Adenomatous-Polyposis-Coli (APC)-Rho-Guanine-Nucleotide-Exchange-Factor-4 (Asef) Interaction. — J Med Chem

Clinical trials (associated diseases)

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