ARHGEF10

Summary

ARHGEF10 (Rho guanine nucleotide exchange factor 10, HGNC:14103) is a protein-coding gene on chromosome 8p23.3, encoding Rho guanine nucleotide exchange factor 10 (O15013). May play a role in developmental myelination of peripheral nerves.

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.

Source: NCBI Gene 9639 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant slowed nerve conduction velocity (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 1,154 total — 18 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 5
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 4 cancer types
• MANE Select transcript: NM_014629

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14103
Approved symbol	ARHGEF10
Name	Rho guanine nucleotide exchange factor 10
Location	8p23.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0294, Gef10
Ensembl gene	ENSG00000104728
Ensembl biotype	protein_coding
OMIM	608136
Entrez	9639

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 17 protein_coding, 5 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000349830, ENST00000382795, ENST00000398560, ENST00000398564, ENST00000518288, ENST00000519641, ENST00000520359, ENST00000520972, ENST00000521927, ENST00000522435, ENST00000522969, ENST00000523596, ENST00000523711, ENST00000523980, ENST00000524212, ENST00000862863, ENST00000862864, ENST00000862865, ENST00000862866, ENST00000926730, ENST00000926731, ENST00000926732, ENST00000926733, ENST00000926734, ENST00000926735, ENST00000926736

RefSeq mRNA: 3 — MANE Select: NM_014629 NM_001308152, NM_001308153, NM_014629

CCDS: CCDS34794, CCDS78296, CCDS78297

Canonical transcript exons

ENST00000349830 — 29 exons

Exon	Start	End
ENSE00000677403	1933800	1933942
ENSE00000888482	1929286	1929443
ENSE00001262966	1880048	1880164
ENSE00001292189	1925283	1925404
ENSE00001314357	1928427	1928650
ENSE00001373982	1926377	1926463
ENSE00001420941	1823926	1824113
ENSE00001749992	1857960	1858115
ENSE00002126628	1956749	1958641
ENSE00003465063	1898433	1898525
ENSE00003479127	1843353	1843436
ENSE00003494067	1859897	1860184
ENSE00003504693	1869194	1869250
ENSE00003512934	1885601	1885707
ENSE00003536131	1893569	1893646
ENSE00003541909	1896333	1896449
ENSE00003559618	1923774	1923874
ENSE00003599065	1922964	1923079
ENSE00003605459	1864373	1864436
ENSE00003612713	1903281	1903451
ENSE00003613529	1945481	1945655
ENSE00003618189	1905571	1905716
ENSE00003619072	1923468	1923595
ENSE00003619778	1952705	1952827
ENSE00003625883	1876571	1876734
ENSE00003639801	1882635	1882749
ENSE00003669657	1894393	1894572
ENSE00003689622	1909295	1909470
ENSE00003728030	1866526	1866602

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.7633 / max 108.5483, expressed in 1424 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87181	6.2011	1412
87182	0.2899	124
87185	0.1671	16
87183	0.0732	19
87184	0.0320	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	98.61	gold quality
tibial nerve	UBERON:0001323	96.97	gold quality
right lung	UBERON:0002167	93.57	gold quality
corpus callosum	UBERON:0002336	93.28	gold quality
apex of heart	UBERON:0002098	91.61	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.96	gold quality
upper lobe of left lung	UBERON:0008952	90.65	gold quality
ascending aorta	UBERON:0001496	90.60	gold quality
thoracic aorta	UBERON:0001515	90.56	gold quality
mucosa of stomach	UBERON:0001199	90.51	gold quality
right testis	UBERON:0004534	90.17	gold quality
descending thoracic aorta	UBERON:0002345	90.03	gold quality
left testis	UBERON:0004533	89.99	gold quality
calcaneal tendon	UBERON:0003701	89.96	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.64	gold quality
lower esophagus	UBERON:0013473	89.59	gold quality
lung	UBERON:0002048	89.54	gold quality
testis	UBERON:0000473	89.45	gold quality
left coronary artery	UBERON:0001626	89.41	gold quality
body of uterus	UBERON:0009853	89.41	gold quality
popliteal artery	UBERON:0002250	89.21	gold quality
tibial artery	UBERON:0007610	89.20	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.16	gold quality
myometrium	UBERON:0001296	88.93	gold quality
right coronary artery	UBERON:0001625	88.88	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.88	gold quality
stromal cell of endometrium	CL:0002255	88.24	gold quality
temporal lobe	UBERON:0001871	88.14	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.13	gold quality
amygdala	UBERON:0001876	88.08	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

100 targeting ARHGEF10, 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-8485	100.00	77.57	4731
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-5682	99.89	72.56	1005

Literature-anchored findings (GeneRIF, showing 13)

• data support a role for ARHGEF10 in developmental myelination of peripheral nerves (PMID:14508709)
• Gef10 is the third member of a Rho-specific GEF family with unusual protein architecture (PMID:16896804)
• A novel RhoA-dependent signaling pathway under the control of ARHGEF10 has a pivotal role in the regulation of the cell division cycle. (PMID:19635168)
• The functional single-nucleotide polymorphism of ARHGEF10 confers the susceptibility to atherothrombotic stroke. (PMID:20042462)
• Identification of a negative regulatory region for the exchange activity and characterization of T332I mutant of Rho guanine nucleotide exchange factor 10 (ARHGEF10). (PMID:21719701)
• the rs4376531 polymorphism in the ARHGEF10 gene is a risk factor for atherothrombotic stroke in the Han Chinese population (PMID:21743172)
• A significant association of ARHGEF10 with paclitaxel chemotherapy induced peripheral neuropathy was found. (PMID:26143528)
• Ectopic expression of an N-terminal-truncated ARHGEF10 mutant led to the generation of large vesicle-like structures containing both Rab6 and Rab8. (PMID:27550519)
• This study provided new insights into the roles of ARHGEF10 SNPs rs2280887, rs9657362, and rs4480162 in the development and progression of ischemic stroke in northern Chinese Han population. (PMID:27934548)
• it was suggested that ARHGEF10 is involved in the regulation of Rab6A and Rab8A localization and invasion of breast carcinoma cells, in which Rab8 also acts via regulation of membrane trafficking. (PMID:28448737)
• A single nucleotide polymorphisms (SNPs) associated with higher delta-6 desaturase (D6D) activity within the Rho guanine nucleotide exchange factor 10 (ARHGEF10) gene is potentially altering plasma triglyceride levels. (PMID:29246731)
• this genome-wide scan of cleft lip triads identifies parent-of-origin interaction effects between ANK3 and maternal smoking, and between ARHGEF10 and alcohol consumption (PMID:31372216)
• Treatment of ARHGEF10-depleted cells with the inhibitor dasatinib reduced levels of phospho Src kinase and attenuated motility and invasion in vitro. Together, our data indicate that ARHGEF10 may function as a tumor suppressor in Pancreatic ductal adenocarcinoma (PDAC). (PMID:31477830)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgef10	ENSDARG00000077788
mus_musculus	Arhgef10	ENSMUSG00000071176
rattus_norvegicus	Arhgef10	ENSRNOG00000012561
drosophila_melanogaster	CG43658	FBGN0263706

Paralogs (2): ARHGEF10L (ENSG00000074964), ARHGEF17 (ENSG00000110237)

Protein

Protein identifiers

Rho guanine nucleotide exchange factor 10 — O15013 (reviewed: O15013)

All UniProt accessions (3): O15013, E9PB39, H0YAN8

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in developmental myelination of peripheral nerves.

Post-translational modifications. Methylated at Gln-1338 by N6AMT1.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (5)

UniProt ID	Names	Canonical?
O15013-1	1	yes
O15013-6	2
O15013-7	3
O15013-4	4
O15013-5	5

RefSeq proteins (3): NP_001295081, NP_001295082, NP_055444* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR039919	ARHGEF10/ARHGEF17	Family

Pfam: PF00621, PF19056, PF19057

UniProt features (29 total): splice variant 5, compositionally biased region 4, modified residue 4, region of interest 4, sequence variant 4, sequence conflict 4, chain 1, domain 1, mutagenesis site 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15013-F1	65.56	0.35

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 (4): 180, 379, 1287, 1338

Mutagenesis-validated functional residues (1):

Position	Phenotype
1338	abolishes methylation by n6amt1.

Function

Pathways and Gene Ontology

Reactome pathways

16 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-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 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: 272 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_CHROMOSOME_ORGANIZATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_GLIAL_CELL_DEVELOPMENT, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, GOBP_NEUROGENESIS, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, CHANDRAN_METASTASIS_DN

GO Biological Process (7): myelination in peripheral nervous system (GO:0022011), actin cytoskeleton organization (GO:0030036), positive regulation of Rho protein signal transduction (GO:0035025), regulation of small GTPase mediated signal transduction (GO:0051056), centrosome duplication (GO:0051298), positive regulation of stress fiber assembly (GO:0051496), mitotic spindle assembly (GO:0090307)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), kinesin binding (GO:0019894), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
RHO GTPase cycle	5
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	2
Schwann cell development	1
peripheral nervous system axon ensheathment	1
myelination	1
cytoskeleton organization	1
actin filament-based process	1
Rho protein signal transduction	1
regulation of Rho protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
centrosome cycle	1
cell cycle process	1
positive regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
mitotic sister chromatid segregation	1
mitotic spindle organization	1
spindle assembly	1
mitotic nuclear division	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
cytoskeletal protein binding	1
binding	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1

Protein interactions and networks

STRING

900 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGEF10	RAB8A	P24407	653
ARHGEF10	RNMT	O43148	598
ARHGEF10	GJB1	P08034	593
ARHGEF10	CLN8	Q9UBY8	546
ARHGEF10	RAB6A	P20340	532
ARHGEF10	DLGAP2	Q9P1A6	529
ARHGEF10	RAB3GAP1	Q15042	520
ARHGEF10	ARHGEF33	A8MVX0	512
ARHGEF10	SH3TC2	Q8TF17	505
ARHGEF10	ARHGEF2	Q92974	499
ARHGEF10	NDRG1	Q92597	494
ARHGEF10	ARHGEF28	Q8N1W1	490
ARHGEF10	SBF2	Q86WG5	480
ARHGEF10	MTMR2	Q13614	476
ARHGEF10	FBXO25	Q8TCJ0	446
ARHGEF10	ARHGEF12	Q9NZN5	446

IntAct

50 interactions, top by confidence:

A	B	Type	Score
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
ARHGEF10	KIF3B	psi-mi:“MI:0915”(physical association)	0.540
KIF3B	ARHGEF10	psi-mi:“MI:0914”(association)	0.540
KIF3B	ARHGEF10	psi-mi:“MI:0915”(physical association)	0.540
SSBP2	CLEC18A	psi-mi:“MI:0914”(association)	0.530
CRK	ARHGAP42	psi-mi:“MI:0914”(association)	0.530
SPSB2	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
SPSB4	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
HSPA8	ARHGEF10	psi-mi:“MI:2364”(proximity)	0.480
ARHGEF10	HMGA1	psi-mi:“MI:0915”(physical association)	0.400
WDR48	UNC13B	psi-mi:“MI:0914”(association)	0.350
HECTD1	METTL15	psi-mi:“MI:0914”(association)	0.350
SPSB4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
ARHGEF10L	ARHGEF10	psi-mi:“MI:0914”(association)	0.350
HSPA12A	ARHGEF10	psi-mi:“MI:0914”(association)	0.350
ARHGEF10	DNAJB5	psi-mi:“MI:0914”(association)	0.350
INF2	PIPSL	psi-mi:“MI:0914”(association)	0.350
PLEKHG7	MROH6	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
UBXN6	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
KLHL14	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
ARHGEF10L	WASL	psi-mi:“MI:0914”(association)	0.350
BAG2	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
GGH	MANBA	psi-mi:“MI:0914”(association)	0.350
SPSB4	BTAF1	psi-mi:“MI:0914”(association)	0.350
ARHGEF10	ICAM1	psi-mi:“MI:0914”(association)	0.350

BioGRID (121): ARHGEF10 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), DNAJB5 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), RSPRY1 (Affinity Capture-MS), RNF31 (Affinity Capture-MS), CCDC88A (Affinity Capture-MS), CBWD3 (Affinity Capture-MS), CBWD3 (Affinity Capture-MS), ARHGEF10 (Affinity Capture-MS), DNAJB5 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), RNF31 (Affinity Capture-MS), ARHGEF10 (Affinity Capture-MS), RSPRY1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8M9QN10, A1L1G9, A2BGA0, A3KN19, A4QP72, A6H8H2, B0BF33, B0JZV4, E7FDW2, F1QJF4, F7BJB9, O15013, O73630, P19838, P25799, P51448, P59997, P68907, P98150, Q04861, Q08AE8, Q12923, Q1LYM3, Q3U1T9, Q5SWY7, Q5VZ89, Q5XGY0, Q5XK72, Q63369, Q64512, Q66JF7, Q69ZS0, Q6F3J0, Q6PF42, Q6ZUJ8, Q7SYN5, Q7Z3E5, Q7Z401, Q803Q4, Q8C033

Diamond homologs: A2AWP8, E9PSK7, O15013, P34609, P52734, P98174, Q07139, Q1ZXH8, Q29RM4, Q58A65, Q5R5M3, Q8C033, Q9ESN9, Q9H8V3, Q9HCE6, Q9UPT6, Q5JSP0, Q5R5T1, Q8BY35, A1L390, A5D7D1, D3ZHA0, D3ZHV2, L7UZ85, O13728, O42287, O43707, O75369, O75689, O76329, O88387, O88990, P05094, P05095, P11277, P11533, P12814, P13466, P15508, P18091

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ARHGEF10	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
ARHGEF10	“up-regulates activity”	RAC1	“guanine nucleotide exchange factor”
ARHGEF10	“up-regulates activity”	CDC42	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 65 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
Constitutive Signaling by Aberrant PI3K in Cancer	5	14.8×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor protein tyrosine kinase signaling pathway	7	21.7×	2e-05
protein autophosphorylation	6	15.6×	4e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 4 cancer types — BLCA, CSCC, NSCLC, SCLC.

Clinical variants and AI predictions

ClinVar

1154 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	3
Uncertain significance	644
Likely benign	280
Benign	130

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
145578	GRCh38/hg38 8p23.3-23.2(chr8:241530-3212774)x1	Pathogenic
147569	GRCh38/hg38 8p23.3-23.2(chr8:241530-3331813)x1	Pathogenic
152253	GRCh38/hg38 8p23.3(chr8:226452-2017223)x1	Pathogenic
1807783	GRCh37/hg19 8p23.3-23.2(chr8:158049-5033424)x1	Pathogenic
1808425	GRCh37/hg19 8p23.3-23.2(chr8:158049-4608757)x1	Pathogenic
3063018	GRCh37/hg19 8p23.3-23.2(chr8:158048-5813459)x1	Pathogenic
32497	GRCh38/hg38 8p23.3(chr8:244617-2017223)x1	Pathogenic
3391901	GRCh37/hg19 8p23.3-23.2(chr8:158049-3936904)x1	Pathogenic
442698	GRCh37/hg19 8p23.3-23.2(chr8:158048-6004205)x1	Pathogenic
443920	GRCh37/hg19 8p23.3-23.2(chr8:158048-5474927)x1	Pathogenic
563540	GRCh37/hg19 8p23.3-23.2(chr8:158048-4847772)x1	Pathogenic
60328	GRCh38/hg38 8p23.3(chr8:202100-2017223)x1	Pathogenic
60342	GRCh38/hg38 8p23.3-23.2(chr8:241530-3701826)x1	Pathogenic
60346	GRCh38/hg38 8p23.3(chr8:1739267-1891412)x1	Pathogenic
688425	GRCh37/hg19 8p23.3-23.1(chr8:158048-6219809)x1	Pathogenic
815067	GRCh37/hg19 8p23.3-23.2(chr8:158048-4188901)x1	Pathogenic
979225	GRCh37/hg19 8p23.3-23.1(chr8:411691-6999114)x1	Pathogenic
980867	GRCh37/hg19 8p23.3(chr8:158048-2081207)x1	Pathogenic
148183	GRCh38/hg38 8p23.3-23.2(chr8:226452-3189683)x1	Likely pathogenic
155587	GRCh38/hg38 8p23.3-23.2(chr8:208048-5615542)x1	Likely pathogenic
625667	GRCh37/hg19 8p23.3(chr8:184617-2136799)	Likely pathogenic

SpliceAI

7749 predictions. Top by Δscore:

Variant	Effect	Δscore
8:1857954:TTTTA:T	acceptor_loss	1.0000
8:1857957:TA:T	acceptor_loss	1.0000
8:1857958:A:AC	acceptor_loss	1.0000
8:1857958:A:AG	acceptor_gain	1.0000
8:1857959:G:GG	acceptor_gain	1.0000
8:1857959:GA:G	acceptor_gain	1.0000
8:1857959:GAA:G	acceptor_gain	1.0000
8:1857959:GAAA:G	acceptor_gain	1.0000
8:1857959:GAAAA:G	acceptor_gain	1.0000
8:1866523:A:AG	acceptor_gain	1.0000
8:1866523:AAGT:A	acceptor_gain	1.0000
8:1866524:A:AG	acceptor_gain	1.0000
8:1866525:G:GG	acceptor_gain	1.0000
8:1866525:GT:G	acceptor_gain	1.0000
8:1866525:GTGAA:G	acceptor_gain	1.0000
8:1866598:GGAGA:G	donor_gain	1.0000
8:1866599:GAGA:G	donor_gain	1.0000
8:1866599:GAGAG:G	donor_gain	1.0000
8:1866600:A:T	donor_gain	1.0000
8:1866601:GA:G	donor_gain	1.0000
8:1866603:G:GG	donor_gain	1.0000
8:1882631:GCA:G	acceptor_loss	1.0000
8:1882632:CA:C	acceptor_loss	1.0000
8:1882633:A:AG	acceptor_gain	1.0000
8:1882634:G:GG	acceptor_gain	1.0000
8:1882727:G:GT	donor_gain	1.0000
8:1882748:GG:G	donor_gain	1.0000
8:1882749:GG:G	donor_gain	1.0000
8:1882776:G:T	donor_gain	1.0000
8:1885598:A:AG	acceptor_gain	1.0000

AlphaMissense

8866 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:1894511:T:C	L485P	1.000
8:1894531:T:A	W492R	1.000
8:1894531:T:C	W492R	1.000
8:1894533:G:C	W492C	1.000
8:1894533:G:T	W492C	1.000
8:1894552:G:C	G499R	1.000
8:1894553:G:A	G499D	1.000
8:1903288:T:C	L578P	1.000
8:1903339:T:C	L595P	1.000
8:1903348:T:C	L598P	1.000
8:1909344:T:A	W698R	1.000
8:1909344:T:C	W698R	1.000
8:1945584:T:C	L1134P	1.000
8:1893576:G:C	R422T	0.999
8:1893577:A:C	R422S	0.999
8:1893577:A:T	R422S	0.999
8:1893579:G:C	R423T	0.999
8:1893579:G:T	R423I	0.999
8:1893630:T:C	L440P	0.999
8:1894520:G:C	R488P	0.999
8:1894532:G:C	W492S	0.999
8:1894550:T:A	I498K	0.999
8:1894552:G:T	G499C	0.999
8:1894553:G:T	G499V	0.999
8:1894562:T:C	F502S	0.999
8:1896333:T:C	F506L	0.999
8:1896334:T:C	F506S	0.999
8:1896335:T:A	F506L	0.999
8:1896335:T:G	F506L	0.999
8:1898497:G:C	R566T	0.999

dbSNP variants (sampled 300 via entrez): RS1000016136 (8:1914437 C>T), RS1000017105 (8:1829807 G>C), RS1000037426 (8:1843057 C>A,T), RS1000039005 (8:1826411 CTGTG>C,CTG,CTGTGTG), RS1000065901 (8:1846033 T>C), RS1000069561 (8:1898837 C>G,T), RS1000073856 (8:1924156 C>T), RS1000093154 (8:1872983 A>G,T), RS1000132614 (8:1875780 T>C), RS1000162303 (8:1875918 C>G), RS1000172748 (8:1922362 C>T), RS1000208541 (8:1850730 C>G), RS1000210481 (8:1902045 A>G), RS1000226851 (8:1834956 C>T), RS1000249037 (8:1895908 C>A,T)

Disease associations

OMIM: gene MIM:608136 | disease phenotypes: MIM:608236, MIM:256730, MIM:118220, MIM:253300

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant slowed nerve conduction velocity	Moderate	Autosomal dominant
peripheral neuropathy	Limited	Autosomal dominant
hereditary peripheral neuropathy	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autosomal dominant slowed nerve conduction velocity	Limited	AD

Mondo (7): autosomal dominant slowed nerve conduction velocity (MONDO:0011998), neuronal ceroid lipofuscinosis (MONDO:0016295), Charcot-Marie-Tooth disease (MONDO:0015626), spinal muscular atrophy (MONDO:0001516), myopathy (MONDO:0005336), peripheral neuropathy (MONDO:0005244), hereditary peripheral neuropathy (MONDO:0020127)

Orphanet (4): Autosomal dominant slowed nerve conduction velocity (Orphanet:140481), Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000762	Decreased nerve conduction velocity
HP:0003383	Onion bulb formation
HP:0003581	Adult onset
HP:0011096	Peripheral demyelination

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001860_2	Multiple sclerosis	1.000000e-06
GCST002671_9	Toenail selenium levels	2.000000e-06
GCST005669_1	Delta-6 desaturase activity response to n3-polyunsaturated fat supplement	9.000000e-09
GCST006814_4	End-stage renal disease	2.000000e-06
GCST009462_93	Optic disc size	3.000000e-08
GCST009542_3	Cleft lip with or without cleft palate x maternal periconceptional alcohol use interaction (parent of origin effect)	3.000000e-06
GCST010724_15	HOMA-B (corrected for HOMA-IR)	4.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007765	delta-6 desaturase measurement
EFO:0009131	response to polyunsaturated fatty acid supplementation
EFO:0003959	cleft lip
EFO:0005939	parental genotype effect measurement
EFO:0009113	alcohol exposure measurement
EFO:0004469	HOMA-B

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D009134	Muscular Atrophy, Spinal	C10.228.854.468; C10.574.562.500; C10.668.467.500
C564269	Slowed Nerve Conduction Velocity, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs9657362	ARHGEF10		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Arsenic	increases abundance, affects methylation, decreases expression	2
Valproic Acid	decreases expression, increases expression, increases methylation	2
Cyclosporine	decreases expression, decreases methylation	2
Aflatoxin B1	affects methylation, decreases methylation	2
Cadmium Chloride	decreases expression, increases abundance	2
chloroacetaldehyde	decreases expression	1
bisphenol A	affects cotreatment, affects methylation, increases methylation	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
CGP 52608	increases reaction, affects binding	1
2-palmitoylglycerol	increases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
Rosiglitazone	decreases expression	1
Decitabine	increases expression	1
Fulvestrant	affects cotreatment, affects methylation, decreases methylation	1
Cidofovir	decreases expression	1
Acetaminophen	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	decreases expression	1
Clodronic Acid	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Ifosfamide	affects expression	1
Ivermectin	decreases expression	1
Methapyrilene	increases methylation	1
Oxygen	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT01422200	PHASE4	COMPLETED	Flu Vaccine Study in Neuromuscular Patients 2011
NCT05232929	PHASE4	ACTIVE_NOT_RECRUITING	Long-term Follow-up Study of Risdiplam in Participants With Spinal Muscular Atrophy (SMA)
NCT05522361	PHASE4	ACTIVE_NOT_RECRUITING	Risdiplam in Patients With Spinal Muscular Atrophy Previously Treated With Nusinersen
NCT07448610	PHASE4	NOT_YET_RECRUITING	ASsessing The REAl-world Safety & Effectiveness of Spinal Muscular Atrophy Participants Treated With Intrathecal Onasemnogene Abeparvovec-brve (OAV101B) (ITVISMA®): A U.S. Pragmatic Multicenter Study (STREAM)
NCT00120055	PHASE4	COMPLETED	Association Between Systemic Exposure of Atorvastatin and Metabolites and Atorvastatin-induced Myotoxicity
NCT03633565	PHASE4	UNKNOWN	Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy