ARHGEF10

protein-coding

Rho guanine nucleotide exchange factor 10, the group of Dbl family Rho GEFs

Gene summary

This gene encodes a Rho guanine nucleotide exchange factor (GEF). Rho GEFs regulate the activity of small Rho GTPases by stimulating the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) and may play a role in neural morphogenesis. Mutations in this gene are associated with slowed nerve conduction velocity (SNCV). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

MANE transcript

NM_014629.4

Inheritance

ClinVar variants

U:574B:266

Top phenotype

Slowed nerve conduction velocity, autosomal dominant (Hereditary motor and sensory neuropathy)

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr8:1,823,926-1,958,641

External References & Databases

Ensembl (ENSG00000104728)

Transcript & Mutation Effects

hg38 • Region Span ~134.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary peripheral neuropathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0020127

Submitter: Ambry Genetics

autosomal dominant slowed nerve conduction velocityLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011998

Submitter: ClinGen

ARHGEF10 was first described in 2003 in a Belgian family with slowed nerve conduction velocities and onion bulb formations with an autosomal dominant inheritance pattern (Verhoeven et al., PMID: 14508709). Clinically, the affected individuals did not develop a clinical Charcot-Marie-Tooth (CMT) phenotype, but an electrophysiological phenotype of NCV slowing (Nelis et al., PMID: 9678704; de Jonghe et al., PMID: 10520946). With a LOD score of 9.93, the variant p.Thr332Ile co-segregated in 12 affected family members (Verhoeven et al., PMID: 14508709) and is supported by functional evidence (Chaya et al., PMID: 21719701). Due to incomplete phenotype and lacking co-segregation and functional evidence, other reported variants (e.g. PMID: 24627108) did not further support the gene-disease relationship. ARHGEF10 encodes a Rho guanine nucleotide exchange factor involved in actin cytoskeleton organization and vesicle trafficking. Rho GTPase pathways and membrane recycling are both common mechanisms in hereditary neuropathies. In an immunofluorescence assay of HeLa cells, ARHGEF10 colocalized with exocytotic vesicle proteins (Shibata et al., PMID: 27550519). Genome-wide association studies performed in 4074 dogs with a profound CMT phenotype revealed biallelic loss-of-function mutations in ARHGEF10 in 1.3% of the cases (Ekenstedt et al., PMID: 25275565). In contrast to this, knock-out mice did not develop a clear neuropathy (Lu et al., PMID: 29456827). In patients, a constitutive activation of the Rho GTPase is hypothesized as the underlying gain-of-function mechanism (Chaya et al., PMID: 21719701). However with one affected family only, the overall evidence to establish a clear gene-disease relationship has not been upheld over time. The panel therefore classifies ARHGEF10 in the category “Limited evidence”. **Recuration Update**: No new literature evidence was found in 2026 so the classification remains unmodified.

autosomal dominant slowed nerve conduction velocitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011998

Submitter: Orphanet

autosomal dominant slowed nerve conduction velocityMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011998

Submitter: PanelApp Australia

peripheral neuropathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005244

Submitter: Ambry Genetics

autosomal dominant slowed nerve conduction velocityLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011998

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Slowed nerve conduction velocity, autosomal dominant (Hereditary motor and sensory neuropathy)AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 9678704; 14508709

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARHGEF10 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 776

not specifiedTotal: 392

ARHGEF10-related disorderTotal: 48

Autosomal dominant slowed nerve conduction velocityTotal: 39

Charcot-Marie-Tooth diseaseTotal: 3

Spinal muscular atrophyTotal: 1

MyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014629.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	187 clinvar	10 clinvar	207
missense			530 clinvar	64 clinvar	4 clinvar	598
nonsense			15 clinvar			15
start loss						0
frameshift			10 clinvar	1 clinvar		11
splice donor/acceptor (+/-2bp)			9 clinvar			9
Total	0	0	574	252	14	840

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014629.4	RefSeq	NP_055444.2	28	MANE Select
ENST00000349830.8	Ensembl	ENSP00000340297.3	28	MANE Select
NM_001308152.2	RefSeq	NP_001295081.1	27	Standard
NM_001308153.3	RefSeq	NP_001295082.2	28	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling by GPCR
Signal Transduction
Rho GTPase cycle
Signaling by Rho GTPases
NRAGE signals death through JNK

Biological Process

myelination in peripheral nervous system
actin cytoskeleton organization
regulation of Rho protein signal transduction
centrosome duplication
positive regulation of stress fiber assembly

Molecular Function

guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity
protein binding
kinesin binding

Cellular Component

centrosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000349830
Coding exons: 28
Length: 134666
Individuals with no LoFs: 125611
Homozygous LoFs: 0
Heterozygous LoFs: 137
Defined: 125748
p: 0.000545

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-2.72	1013	797	1.27	0.0000515	8822
Missense (PolyPhen)		355	327.32	1.0846		3595
Synonymous	-5.54	471	341	1.38	0.0000270	2598
Loss of Function	1.72	54	69.4	0.778	0.00000369	808

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00058	0.00058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00038	rare
Finnish	0.00060	0.00060	rare
European (Non-Finnish)	0.00056	0.00055	rare
South Asian	0.00075	0.00075	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in developmental myelination of peripheral nerves. {ECO:0000269|PubMed:14508709}.;
Disease: DISEASE: Slowed nerve conduction velocity (SNCV) [MIM:608236]: Affected individuals present a reduction in nerve conduction velocities without any clinical signs of peripheral or central nervous system dysfunction. SNCV inheritance is autosomal dominant. {ECO:0000269|PubMed:14508709}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.799
RVIS EVS: -1.02
RVIS percentile EVS: 8.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.657

Gene Damage Prediction

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