ARHGEF4

Rho guanine nucleotide exchange factor 4, the group of Dbl family Rho GEFs|Pleckstrin homology domain containing

Basic information

Region (hg38): 2:130836914-131047263

Links

ENSG00000136002 ∙ NCBI:50649 ∙ OMIM:605216 ∙ HGNC:684 ∙ Uniprot:Q9NR80 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ARHGEF4 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ARHGEF4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				4	3	7
missense			39	10	4	53
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region					1	1
non coding				1		1
Total	0	0	39	15	7

Variants in ARHGEF4

This is a list of pathogenic ClinVar variants found in the ARHGEF4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-130915834-G-A			Likely benign (Dec 01, 2023)
2-130916381-G-A			Likely benign (Dec 01, 2023)
2-130930967-G-A		not specified	Uncertain significance (Aug 23, 2021)
2-130931014-G-A		ARHGEF4-related disorder	Benign (Oct 24, 2019)
2-130931019-A-G		not specified	Uncertain significance (Apr 07, 2023)
2-130931021-A-T		not specified	Uncertain significance (Oct 26, 2022)
2-130931030-G-T		not specified	Uncertain significance (Feb 22, 2023)
2-130931100-G-A		not specified	Likely benign (Mar 01, 2023)
2-130931108-G-T		not specified	Uncertain significance (Apr 04, 2023)
2-130931121-C-T		not specified	Uncertain significance (Dec 01, 2023)
2-130931138-C-T		not specified	Uncertain significance (Nov 12, 2021)
2-130931142-C-T		not specified	Uncertain significance (Apr 19, 2023)
2-130931147-G-A		ARHGEF4-related disorder • not specified	Likely benign (Sep 01, 2021)
2-130931207-C-A		not specified	Uncertain significance (Nov 30, 2022)
2-130931209-C-T		ARHGEF4-related disorder	Likely benign (Feb 28, 2019)
2-130931210-G-A		ARHGEF4-related disorder	Benign (Oct 25, 2019)
2-130931243-A-C		not specified	Uncertain significance (May 04, 2023)
2-130946565-C-G		not specified	Uncertain significance (Aug 04, 2023)
2-130946590-A-G		not specified	Uncertain significance (Apr 07, 2022)
2-130946613-G-C			Benign (Jan 25, 2018)
2-130946624-C-A		not specified	Uncertain significance (Aug 04, 2023)
2-130946630-G-C		not specified	Uncertain significance (Jun 02, 2023)
2-130946635-G-A		ARHGEF4-related disorder	Likely benign (Mar 21, 2019)
2-130946644-C-T		ARHGEF4-related disorder	Likely benign (Jun 07, 2019)
2-131011860-C-T			Likely benign (Dec 01, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ARHGEF4	protein_coding	protein_coding	ENST00000326016	12	210348

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000736	0.999	125732	0	16	125748	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.33	361	439	0.822	0.0000279	4546
Missense in Polyphen		121	195.18	0.61993		2095
Synonymous	0.111	178	180	0.989	0.0000124	1290
Loss of Function	3.62	12	35.2	0.341	0.00000166	371

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000590	0.0000590
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.0000887	0.0000879
Middle Eastern	0.000163	0.000163
South Asian	0.0000654	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as 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. {ECO:0000269|PubMed:10947987, ECO:0000269|PubMed:12598901, ECO:0000269|PubMed:17145773, ECO:0000269|PubMed:17599059, ECO:0000269|PubMed:19893577}.
• Pathway: Regulation of actin cytoskeleton - Homo sapiens (human);Regulation of Actin Cytoskeleton;Signaling by GPCR;Signal Transduction;Rho GTPase cycle;Signaling by Rho GTPases;EGFR1;NRAGE signals death through JNK;Death Receptor Signalling;p75 NTR receptor-mediated signalling;G alpha (12/13) signalling events;Wnt;GPCR downstream signalling;Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met);Cell death signalling via NRAGE, NRIF and NADE (Consensus)

Intolerance Scores

• loftool: 0.306
• rvis_EVS: -0.55
• rvis_percentile_EVS: 19.93

Haploinsufficiency Scores

• pHI: 0.313
• hipred: Y
• hipred_score: 0.586
• ghis: 0.561

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.487

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Arhgef4
• Phenotype: skeleton phenotype; immune system phenotype; digestive/alimentary phenotype; neoplasm; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Gene ontology

• Biological process: G protein-coupled receptor signaling pathway;lamellipodium assembly;regulation of Rho protein signal transduction;intracellular signal transduction;positive regulation of apoptotic process;filopodium assembly;regulation of small GTPase mediated signal transduction
• Cellular component: cytosol;ruffle membrane
• Molecular function: guanyl-nucleotide exchange factor activity;Rho guanyl-nucleotide exchange factor activity;protein binding;protein domain specific binding;Rac guanyl-nucleotide exchange factor activity