Neuronopathy, distal hereditary motor, autosomal recessive 10

Summary

Neuronopathy, distal hereditary motor, autosomal recessive 10 (MONDO:0957876) is a disease caused by VRK1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: VRK1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, autosomal recessive 10
Mondo ID	MONDO:0957876
OMIM	620542
DOID	DOID:0081429
UMLS	C5882703
MedGen	1846713
GARD	0026890
Is cancer (heuristic)	no

Data availability: 27 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › neuronopathy, distal hereditary motor, autosomal recessive › neuronopathy, distal hereditary motor, autosomal recessive 10

Related subtypes (11): autosomal recessive distal spinal muscular atrophy 1, autosomal recessive distal spinal muscular atrophy 2, neuronopathy, distal hereditary motor, autosomal recessive 3, neuronopathy, distal hereditary motor, autosomal recessive 4, neuronopathy, distal hereditary motor, autosomal recessive 5, neuronopathy, distal hereditary motor, autosomal recessive 8, neuronopathy, distal hereditary motor, autosomal recessive 7, early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome, spinal muscular atrophy, distal, autosomal recessive, 6, neuronopathy, distal hereditary motor, autosomal recessive 9, neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity

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

27 retrieved; paginated sample, class counts are floors:

9 pathogenic/likely pathogenic, 6 likely pathogenic, 6 conflicting classifications of pathogenicity, 5 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1453431	NM_003384.3(VRK1):c.1124G>A (p.Trp375Ter)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1970380	NM_003384.3(VRK1):c.1144dup (p.Glu382fs)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209204	NM_003384.3(VRK1):c.356A>G (p.His119Arg)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209205	NM_003384.3(VRK1):c.961C>T (p.Arg321Cys)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2164156	NM_003384.3(VRK1):c.1081_1084del (p.Glu361fs)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
464942	NM_003384.3(VRK1):c.883_886del (p.Lys295fs)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
521856	NM_003384.3(VRK1):c.1160G>A (p.Arg387His)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7497	NM_003384.3(VRK1):c.1072C>T (p.Arg358Ter)	VRK1	Pathogenic	criteria provided, multiple submitters, no conflicts
846403	NM_003384.3(VRK1):c.660T>A (p.Cys220Ter)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
848771	NM_003384.3(VRK1):c.1159+1G>A	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1505827	NM_003384.3(VRK1):c.1094del (p.Ser365fs)	VRK1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3576914	NM_003384.3(VRK1):c.3dup (p.Pro2fs)	VRK1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3576915	NM_003384.3(VRK1):c.287-2A>G	VRK1	Likely pathogenic	criteria provided, single submitter
3576916	NM_003384.3(VRK1):c.882del (p.Asn294fs)	VRK1	Likely pathogenic	criteria provided, single submitter
3780789	NM_003384.3(VRK1):c.286+2T>G	VRK1	Likely pathogenic	criteria provided, single submitter
4291770	NM_003384.3(VRK1):c.865dup (p.Cys289fs)	VRK1	Likely pathogenic	criteria provided, single submitter
197213	NM_003384.3(VRK1):c.266G>A (p.Arg89Gln)	VRK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218924	NM_003384.3(VRK1):c.706G>A (p.Val236Met)	VRK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30243	NM_003384.3(VRK1):c.397C>T (p.Arg133Cys)	VRK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533538	NM_003384.3(VRK1):c.6del (p.Arg3fs)	VRK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
617789	NM_003384.3(VRK1):c.761G>T (p.Trp254Leu)	VRK1	Conflicting classifications of pathogenicity	no assertion criteria provided
619020	NM_003384.3(VRK1):c.656G>T (p.Arg219Ile)	VRK1	Conflicting classifications of pathogenicity	no assertion criteria provided
1251999	NM_003384.3(VRK1):c.236C>T (p.Pro79Leu)	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1977286	NM_003384.3(VRK1):c.512A>G (p.His171Arg)	VRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3775425	NM_003384.3(VRK1):c.574C>A (p.Gln192Lys)	VRK1	Uncertain significance	criteria provided, single submitter
3775426	NM_003384.3(VRK1):c.248A>G (p.Glu83Gly)	VRK1	Uncertain significance	criteria provided, single submitter
4277661	NM_003384.3(VRK1):c.665A>G (p.Asp222Gly)	VRK1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
VRK1	Strong	Autosomal recessive	neuronopathy, distal hereditary motor, autosomal recessive 10	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VRK1	Orphanet:2254	Pontocerebellar hypoplasia type 1
VRK1	Orphanet:423894	Microcephaly-complex motor and sensory axonal neuropathy syndrome

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
VRK1	HGNC:12718	ENSG00000100749	Q99986	Serine/threonine-protein kinase VRK1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VRK1	Serine/threonine-protein kinase VRK1	Serine/threonine kinase involved in the regulation of key cellular processes including the cell cycle, nuclear condensation, transcription regulation, and DNA damage response.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VRK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

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
bone marrow	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VRK1	286	ubiquitous	marker	oocyte, bone marrow, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VRK1	3,022

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VRK1	Q99986	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Initiation of Nuclear Envelope (NE) Reformation	1	601.0×	0.002	VRK1
Nuclear Envelope Breakdown	1	456.8×	0.002	VRK1

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
positive regulation of protein localization to chromatin	1	5617.3×	0.001	VRK1
Cajal body organization	1	4213.0×	0.001	VRK1
Golgi disassembly	1	2808.7×	0.001	VRK1
mitotic nuclear membrane disassembly	1	1872.4×	0.002	VRK1
regulation of neuron migration	1	624.1×	0.004	VRK1
protein autophosphorylation	1	145.3×	0.014	VRK1
neuron projection development	1	122.1×	0.014	VRK1
chromatin remodeling	1	73.0×	0.020	VRK1
protein phosphorylation	1	68.0×	0.020	VRK1
DNA damage response	1	53.5×	0.022	VRK1
cell division	1	46.2×	0.024	VRK1
signal transduction	1	16.1×	0.062	VRK1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VRK1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
VRK1	74	Binding:74

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	1	VRK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
VRK1	74	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.