neuronopathy, distal hereditary motor, type 2A

Summary

neuronopathy, distal hereditary motor, type 2A (MONDO:0008025) is a disease caused by HSPB8 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: HSPB8 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 40

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, type 2A
Mondo ID	MONDO:0008025
MeSH	C563561
OMIM	158590
DOID	DOID:0111208
UMLS	C1834692
MedGen	322471
GARD	0018262
Is cancer (heuristic)	no

Also known as: HMN2A · HSPB8 neuronopathy, distal hereditary motor · neuronopathy, distal hereditary motor caused by mutation in HSPB8 · neuronopathy, distal hereditary motor, type IIA

Data availability: 40 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › neuronopathy, distal hereditary motor, autosomal dominant › distal hereditary motor neuropathy type 2 › neuronopathy, distal hereditary motor, type 2A

Related subtypes (3): neuronopathy, distal hereditary motor, type 2B, neuronopathy, distal hereditary motor, type 2C, neuronopathy, distal hereditary motor, type 2D

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

40 retrieved; paginated sample, class counts are floors:

17 uncertain significance, 12 benign, 4 benign/likely benign, 3 conflicting classifications of pathogenicity, 2 pathogenic, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2617	NM_014365.3(HSPB8):c.423G>C (p.Lys141Asn)	HSPB8	Pathogenic	no assertion criteria provided
2618	NM_014365.3(HSPB8):c.421A>G (p.Lys141Glu)	HSPB8	Pathogenic	criteria provided, multiple submitters, no conflicts
977157	NM_014365.3(HSPB8):c.562del (p.Gln188fs)	HSPB8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
560411	NM_014365.3(HSPB8):c.413A>C (p.Asn138Thr)	HSPB8	Likely pathogenic	criteria provided, single submitter
464510	NM_014365.3(HSPB8):c.432-10T>A	HSPB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
567484	NM_014365.3(HSPB8):c.14A>G (p.Gln5Arg)	HSPB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880624	NM_014365.3(HSPB8):c.163C>T (p.Arg55Cys)	HSPB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027861	NM_014365.3(HSPB8):c.403G>C (p.Val135Leu)	HSPB8	Uncertain significance	criteria provided, single submitter
307409	NM_014365.2(HSPB8):c.-489G>A	HSPB8	Uncertain significance	criteria provided, single submitter
307410	NM_014365.2(HSPB8):c.-480C>G	HSPB8	Uncertain significance	criteria provided, single submitter
307412	NM_014365.3(HSPB8):c.-314T>C	HSPB8	Uncertain significance	criteria provided, single submitter
307413	NM_014365.3(HSPB8):c.-201G>T	HSPB8	Uncertain significance	criteria provided, multiple submitters, no conflicts
307415	NM_014365.3(HSPB8):c.-172G>C	HSPB8	Uncertain significance	criteria provided, multiple submitters, no conflicts
307420	NM_014365.3(HSPB8):c.*67T>G	HSPB8	Uncertain significance	criteria provided, single submitter
307422	NM_014365.3(HSPB8):c.*504T>C	HSPB8	Uncertain significance	criteria provided, single submitter
307427	NM_014365.3(HSPB8):c.*648A>G	HSPB8	Uncertain significance	criteria provided, single submitter
307430	NM_014365.3(HSPB8):c.*803T>C	HSPB8	Uncertain significance	criteria provided, single submitter
560410	NM_014365.3(HSPB8):c.269C>T (p.Pro90Leu)	HSPB8	Uncertain significance	criteria provided, multiple submitters, no conflicts
881961	NM_014365.2(HSPB8):c.-522C>G	HSPB8	Uncertain significance	criteria provided, single submitter
882104	NM_014365.3(HSPB8):c.*788C>T	HSPB8	Uncertain significance	criteria provided, single submitter
883131	NM_014365.2(HSPB8):c.-419A>T	HSPB8	Uncertain significance	criteria provided, single submitter
883245	NM_014365.3(HSPB8):c.*860T>C	HSPB8	Uncertain significance	criteria provided, single submitter
883984	NM_014365.3(HSPB8):c.*123G>A	HSPB8	Uncertain significance	criteria provided, multiple submitters, no conflicts
883985	NM_014365.3(HSPB8):c.*330A>T	HSPB8	Uncertain significance	criteria provided, single submitter
260402	NM_014365.3(HSPB8):c.402T>C (p.Ile134=)	HSPB8	Benign	criteria provided, multiple submitters, no conflicts
260403	NM_014365.3(HSPB8):c.582C>T (p.Thr194=)	HSPB8	Benign	criteria provided, multiple submitters, no conflicts
307411	NM_014365.2(HSPB8):c.-457A>G	HSPB8	Benign	criteria provided, single submitter
307414	NM_014365.3(HSPB8):c.-193T>C	HSPB8	Benign	criteria provided, multiple submitters, no conflicts
307416	NM_014365.3(HSPB8):c.48G>A (p.Leu16=)	HSPB8	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
307417	NM_014365.3(HSPB8):c.266C>G (p.Pro89Arg)	HSPB8	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

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
HSPB8	Strong	Autosomal dominant	neuronopathy, distal hereditary motor, type 2A	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HSPB8	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB8	Orphanet:476093	HSPB8-related autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome
HSPB8	Orphanet:99945	Autosomal dominant Charcot-Marie-Tooth disease type 2L

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
HSPB8	HGNC:30171	ENSG00000152137	Q9UJY1	Heat shock protein beta-8	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HSPB8	Heat shock protein beta-8	Involved in the chaperone-assisted selective autophagy (CASA), a crucial process for protein quality control, particularly in mechanical strained cells and tissues such as muscle.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HSPB8	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone

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
gastrocnemius	1
mucosa of stomach	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HSPB8	284	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, mucosa of stomach, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPB8	1,916

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HSPB8	Q9UJY1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
HSF1-dependent transactivation	1	317.2×	0.003	HSPB8

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 aggrephagy	1	2808.7×	7e-04	HSPB8
cellular response to unfolded protein	1	991.3×	0.001	HSPB8

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
HSPB8	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	HSPB8

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)
HSPB8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.