Neuronopathy, distal hereditary motor, autosomal recessive 5

Summary

Neuronopathy, distal hereditary motor, autosomal recessive 5 (MONDO:0013947) is a disease caused by DNAJB2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DNAJB2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 268

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, autosomal recessive 5
Mondo ID	MONDO:0013947
OMIM	614881
Orphanet	443950
DOID	DOID:0111214
UMLS	C4749918
MedGen	1667915
GARD	0017421
Is cancer (heuristic)	no

Also known as: autosomal recessive distal spinal muscular atrophy type 5 · DNAJB2-related CMT2 · DSMA5 · dSMA5 · Young adult-onset dHMN · young adult-onset distal hereditary motor neuropathy

Data availability: 268 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › spinal muscular atrophy › neuronopathy, distal hereditary motor, autosomal recessive 5

Related subtypes (18): spinal muscular atrophy-progressive myoclonic epilepsy syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, facioscapulohumeral type, adult-onset proximal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, segmental, spinal muscular atrophy, Ryukyuan type, scapuloperoneal spinal muscular atrophy, autosomal recessive, X-linked distal spinal muscular atrophy type 3, infantile-onset X-linked spinal muscular atrophy, 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 dominant, bulbospinal muscular atrophy, spinal muscular atrophy with respiratory distress type 2, proximal spinal muscular atrophy, spinal muscular atrophy type 0

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

268 retrieved; paginated sample, class counts are floors:

124 likely benign, 106 uncertain significance, 14 likely pathogenic, 8 pathogenic, 7 benign, 6 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1441902	NM_006736.6(DNAJB2):c.119_120del (p.Glu40fs)	DNAJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1452257	NM_006736.6(DNAJB2):c.204T>G (p.Tyr68Ter)	DNAJB2	Pathogenic	criteria provided, single submitter
183041	NM_006736.6(DNAJB2):c.229+1G>A	DNAJB2	Pathogenic	criteria provided, single submitter
1895597	NM_006736.6(DNAJB2):c.118G>T (p.Glu40Ter)	DNAJB2	Pathogenic	criteria provided, single submitter
217886	NM_006736.6(DNAJB2):c.352+1G>A	DNAJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
246691	NM_006736.6(DNAJB2):c.620-1G>A	DNAJB2	Pathogenic	criteria provided, single submitter
254212	NM_001039550.2(DNAJB2):c.0_229+18del	DNAJB2	Pathogenic	criteria provided, single submitter
652811	NM_006736.6(DNAJB2):c.175+2T>A	DNAJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
864789	NM_006736.6(DNAJB2):c.394C>T (p.Arg132Ter)	DNAJB2	Pathogenic	criteria provided, single submitter
1464699	NM_006736.6(DNAJB2):c.446-1G>A	DNAJB2	Likely pathogenic	criteria provided, single submitter
1709938	NM_006736.6(DNAJB2):c.65+1G>A	DNAJB2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
183042	NM_006736.6(DNAJB2):c.14A>G (p.Tyr5Cys)	DNAJB2	Likely pathogenic	criteria provided, single submitter
243085	NM_006736.6(DNAJB2):c.310del (p.Arg104fs)	DNAJB2	Likely pathogenic	criteria provided, single submitter
2696517	NM_006736.6(DNAJB2):c.445+1G>A	DNAJB2	Likely pathogenic	criteria provided, single submitter
2828827	NM_006736.6(DNAJB2):c.353-1G>C	DNAJB2	Likely pathogenic	criteria provided, single submitter
3376836	NM_006736.6(DNAJB2):c.65+1G>C	DNAJB2	Likely pathogenic	criteria provided, single submitter
3896843	NM_006736.6(DNAJB2):c.175+3A>T	DNAJB2	Likely pathogenic	criteria provided, single submitter
3896844	NM_006736.6(DNAJB2):c.352+1G>C	DNAJB2	Likely pathogenic	criteria provided, single submitter
3896845	NM_006736.6(DNAJB2):c.446-1G>C	DNAJB2	Likely pathogenic	criteria provided, single submitter
4073419	NM_006736.6(DNAJB2):c.159T>G (p.Tyr53Ter)	DNAJB2	Likely pathogenic	no assertion criteria provided
4795860	NM_006736.6(DNAJB2):c.176-2A>G	DNAJB2	Likely pathogenic	criteria provided, single submitter
623377	NM_006736.6(DNAJB2):c.446-2A>G	DNAJB2	Likely pathogenic	criteria provided, single submitter
873313	NM_006736.6(DNAJB2):c.757G>A (p.Glu253Lys)	DNAJB2	Likely pathogenic	criteria provided, single submitter
1447614	NM_006736.6(DNAJB2):c.622G>A (p.Val208Ile)	DNAJB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1732377	NM_006736.6(DNAJB2):c.353-24_357del	DNAJB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234675	NM_006736.6(DNAJB2):c.230-2A>G	DNAJB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
718838	NM_006736.6(DNAJB2):c.385C>T (p.Arg129Trp)	DNAJB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
856608	NM_006736.6(DNAJB2):c.89G>A (p.Trp30Ter)	DNAJB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
917200	NM_006736.6(DNAJB2):c.444C>T (p.Ser148=)	DNAJB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1018274	NM_006736.6(DNAJB2):c.411C>G (p.Phe137Leu)	DNAJB2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
DNAJB2	Strong	Autosomal recessive	neuronopathy, distal hereditary motor, autosomal recessive 5	5
VWA1	Strong	Autosomal recessive	neuronopathy, distal hereditary motor, autosomal recessive 7	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNAJB2	Orphanet:314485	Young adult-onset distal hereditary motor neuropathy
DNAJB2	Orphanet:443950	DNAJB2-related Charcot-Marie-Tooth disease type 2
VWA1	Orphanet:314485	Young adult-onset distal hereditary motor neuropathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DNAJB2	HGNC:5228	ENSG00000135924	P25686	DnaJ homolog subfamily B member 2	gencc,clinvar
VWA1	HGNC:30910	ENSG00000179403	Q6PCB0	von Willebrand factor A domain-containing protein 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNAJB2	DnaJ homolog subfamily B member 2	Functions as a co-chaperone, regulating the substrate binding and activating the ATPase activity of chaperones of the HSP70/heat shock protein 70 family.
VWA1	von Willebrand factor A domain-containing protein 1	Promotes matrix assembly.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNAJB2	Other/Unknown	no		DnaJ_domain, UIM_dom, DnaJ_domain_CS
VWA1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Ig-like_fold

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	2
cerebellar hemisphere	1
right hemisphere of cerebellum	1
lower esophagus muscularis layer	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNAJB2	281	ubiquitous	marker	C1 segment of cervical spinal cord, right hemisphere of cerebellum, cerebellar hemisphere
VWA1	240	ubiquitous	marker	tibial nerve, C1 segment of cervical spinal cord, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNAJB2	2,884
VWA1	1,184

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNAJB2	P25686	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VWA1	Q6PCB0	79.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
Post-translational protein phosphorylation	1	100.2×	0.012	VWA1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	VWA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of protein folding	1	8426.0×	0.002	DNAJB2
negative regulation of protein deubiquitination	1	4213.0×	0.002	DNAJB2
negative regulation of inclusion body assembly	1	842.6×	0.007	DNAJB2
positive regulation of ATP-dependent activity	1	702.2×	0.007	DNAJB2
regulation of protein ubiquitination	1	443.5×	0.008	DNAJB2
behavioral response to pain	1	443.5×	0.008	VWA1
negative regulation of protein binding	1	312.1×	0.008	DNAJB2
protein refolding	1	312.1×	0.008	DNAJB2
neuron cellular homeostasis	1	227.7×	0.010	DNAJB2
response to unfolded protein	1	150.5×	0.013	DNAJB2
positive regulation of protein ubiquitination	1	106.7×	0.015	DNAJB2
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	1	105.3×	0.015	DNAJB2
regulation of protein localization	1	102.8×	0.015	DNAJB2
ERAD pathway	1	90.6×	0.016	DNAJB2
negative regulation of cell growth	1	72.0×	0.018	DNAJB2
extracellular matrix organization	1	61.1×	0.019	VWA1
protein homooligomerization	1	61.1×	0.019	VWA1
protein folding	1	51.7×	0.021	DNAJB2
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.040	DNAJB2
negative regulation of cell population proliferation	1	21.1×	0.047	DNAJB2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
DNAJB2	0	0
VWA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	VWA1
E	Difficult family or no structure, no drug	1	DNAJB2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNAJB2	0	—
VWA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.