Autosomal dominant slowed nerve conduction velocity

Summary

Autosomal dominant slowed nerve conduction velocity (MONDO:0011998) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 47

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		1	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant slowed nerve conduction velocity
Mondo ID	MONDO:0011998
MeSH	C564269
OMIM	608236
Orphanet	140481
SNOMED CT	764854006
UMLS	C1842357
MedGen	330829
GARD	0016962
Is cancer (heuristic)	no

Also known as: autosomal dominant slowed nerve conduction velocity · slowed nerve conduction velocity, AD · slowed nerve conduction velocity, autosomal dominant · SNCV

Data availability: 47 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › hereditary motor and sensory neuropathy › autosomal dominant slowed nerve conduction velocity

Related subtypes (7): polyneuropathy-hand defect syndrome, hereditary thermosensitive neuropathy, hereditary sensorimotor neuropathy with hyperelastic skin, demyelinating hereditary motor and sensory neuropathy, severe early-onset axonal neuropathy due to MFN2 deficiency, hereditary motor and sensory neuropathy with acrodystrophy, hereditary motor and sensory neuropathy type 6

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

47 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 12 benign, 9 conflicting classifications of pathogenicity, 2 likely benign, 2 benign/likely benign, 1 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
1284824	NM_014629.4(ARHGEF10):c.2385C>T (p.Asp795=)	ARHGEF10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156013	NM_014629.4(ARHGEF10):c.1013G>C (p.Arg338Thr)	ARHGEF10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157538	NM_014629.4(ARHGEF10):c.2197C>T (p.His733Tyr)	ARHGEF10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2066601	NM_014629.4(ARHGEF10):c.3644A>G (p.Gln1215Arg)	ARHGEF10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374306	NM_014629.4(ARHGEF10):c.2063G>A (p.Ser688Asn)	ARHGEF10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
388721	NM_014629.4(ARHGEF10):c.2134G>T (p.Ala712Ser)	ARHGEF10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
810874	NM_014629.4(ARHGEF10):c.2909C>T (p.Thr970Met)	ARHGEF10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
810896	NM_014629.4(ARHGEF10):c.401C>T (p.Ala134Val)	ARHGEF10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
993850	NM_014629.4(ARHGEF10):c.3869C>T (p.Ser1290Leu)	ARHGEF10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029283	NM_014629.4(ARHGEF10):c.1343A>G (p.Glu448Gly)	ARHGEF10	Uncertain significance	criteria provided, single submitter
1031837	NM_014629.4(ARHGEF10):c.121G>T (p.Glu41Ter)	ARHGEF10	Uncertain significance	criteria provided, single submitter
1163296	NM_014629.4(ARHGEF10):c.3098A>G (p.Glu1033Gly)	ARHGEF10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1524803	NM_014629.4(ARHGEF10):c.896A>G (p.Asp299Gly)	ARHGEF10	Uncertain significance	criteria provided, single submitter
1678610	NM_014629.4(ARHGEF10):c.990C>A (p.Asp330Glu)	ARHGEF10	Uncertain significance	criteria provided, single submitter
1709815	NM_014629.4(ARHGEF10):c.1076-3_1076-2delinsTG	ARHGEF10	Uncertain significance	criteria provided, single submitter
1709868	NM_014629.4(ARHGEF10):c.1606del (p.Met535_Met536insTer)	ARHGEF10	Uncertain significance	criteria provided, single submitter
2205841	NM_014629.4(ARHGEF10):c.2005T>G (p.Tyr669Asp)	ARHGEF10	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439156	NM_014629.4(ARHGEF10):c.679+2T>A	ARHGEF10	Uncertain significance	criteria provided, single submitter
2439157	NM_014629.4(ARHGEF10):c.1030A>G (p.Lys344Glu)	ARHGEF10	Uncertain significance	criteria provided, single submitter
2526	NM_014629.4(ARHGEF10):c.995C>T (p.Thr332Ile)	ARHGEF10	no classifications from unflagged records	no classifications from unflagged records
2958669	NM_014629.4(ARHGEF10):c.3979C>G (p.Gln1327Glu)	ARHGEF10	Uncertain significance	criteria provided, multiple submitters, no conflicts
3067915	NM_014629.4(ARHGEF10):c.1936G>A (p.Asp646Asn)	ARHGEF10	Uncertain significance	criteria provided, single submitter
3242107	NM_014629.4(ARHGEF10):c.2711C>G (p.Thr904Ser)	ARHGEF10	Uncertain significance	criteria provided, single submitter
453261	NM_014629.4(ARHGEF10):c.133C>T (p.Gln45Ter)	ARHGEF10	Uncertain significance	no assertion criteria provided
590923	NM_014629.4(ARHGEF10):c.1720G>A (p.Glu574Lys)	ARHGEF10	Uncertain significance	no assertion criteria provided
634605	NM_014629.4(ARHGEF10):c.3964_3965dup (p.Arg1323fs)	ARHGEF10	Uncertain significance	criteria provided, single submitter
800357	NM_014629.4(ARHGEF10):c.1081A>T (p.Arg361Ter)	ARHGEF10	Uncertain significance	criteria provided, multiple submitters, no conflicts
812165	NM_014629.4(ARHGEF10):c.1812C>A (p.Tyr604Ter)	ARHGEF10	Uncertain significance	criteria provided, single submitter
816533	NM_014629.4(ARHGEF10):c.343G>T (p.Glu115Ter)	ARHGEF10	Uncertain significance	criteria provided, single submitter
930456	NM_014629.4(ARHGEF10):c.541A>G (p.Thr181Ala)	ARHGEF10	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ARHGEF10	Moderate	Autosomal dominant	autosomal dominant slowed nerve conduction velocity	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARHGEF10	Orphanet:140481	Autosomal dominant slowed nerve conduction velocity

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARHGEF10	HGNC:14103	ENSG00000104728	O15013	Rho guanine nucleotide exchange factor 10	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARHGEF10	Rho guanine nucleotide exchange factor 10	May play a role in developmental myelination of peripheral nerves.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARHGEF10	Scaffold/PPI	no		DH_dom, WD40/YVTN_repeat-like_dom_sf, DBL_dom_sf

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lung	1
sural nerve	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARHGEF10	134	ubiquitous	yes	sural nerve, tibial nerve, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARHGEF10	1,071

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARHGEF10	O15013	65.56

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cell death signalling via NRAGE, NRIF and NADE	1	219.6×	0.017	ARHGEF10
p75 NTR receptor-mediated signalling	1	187.2×	0.017	ARHGEF10
NRAGE signals death through JNK	1	184.2×	0.017	ARHGEF10
RHOB GTPase cycle	1	154.3×	0.017	ARHGEF10
RHOC GTPase cycle	1	146.4×	0.017	ARHGEF10
Death Receptor Signaling	1	139.3×	0.017	ARHGEF10
G alpha (12/13) signalling events	1	137.6×	0.017	ARHGEF10
RHOA GTPase cycle	1	74.6×	0.024	ARHGEF10
CDC42 GTPase cycle	1	72.3×	0.024	ARHGEF10
RAC1 GTPase cycle	1	61.1×	0.024	ARHGEF10
RHO GTPase cycle	1	60.1×	0.024	ARHGEF10
GPCR downstream signalling	1	43.4×	0.031	ARHGEF10
Signaling by GPCR	1	40.1×	0.031	ARHGEF10
Signaling by Rho GTPases	1	34.2×	0.032	ARHGEF10
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.032	ARHGEF10
Signal Transduction	1	10.2×	0.098	ARHGEF10

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
centrosome duplication	1	936.2×	0.004	ARHGEF10
myelination in peripheral nervous system	1	887.0×	0.004	ARHGEF10
positive regulation of Rho protein signal transduction	1	581.1×	0.004	ARHGEF10
mitotic spindle assembly	1	343.9×	0.004	ARHGEF10
positive regulation of stress fiber assembly	1	312.1×	0.004	ARHGEF10
regulation of small GTPase mediated signal transduction	1	144.0×	0.008	ARHGEF10
actin cytoskeleton organization	1	79.1×	0.013	ARHGEF10

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARHGEF10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ARHGEF10

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ARHGEF10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.