neuronopathy, distal hereditary motor, type 2C

Summary

neuronopathy, distal hereditary motor, type 2C (MONDO:0013243) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 64

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, type 2C
Mondo ID	MONDO:0013243
OMIM	613376
DOID	DOID:0111209
UMLS	C3150619
MedGen	461969
GARD	0018264
Is cancer (heuristic)	no

Also known as: HMN2C · HSPB3 neuronopathy, distal hereditary motor · neuronopathy, distal hereditary motor caused by mutation in HSPB3 · neuronopathy, distal hereditary motor, type IIC

Data availability: 64 ClinVar variants · 3 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 2C

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

64 retrieved; paginated sample, class counts are floors:

42 uncertain significance, 12 likely benign, 5 conflicting classifications of pathogenicity, 3 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2886002	NM_006308.3(HSPB3):c.229G>A (p.Val77Met)	HSPB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353901	NM_006308.3(HSPB3):c.347G>C (p.Arg116Pro)	HSPB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
471413	NM_006308.3(HSPB3):c.271G>A (p.Glu91Lys)	HSPB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5429	NM_006308.3(HSPB3):c.21G>T (p.Arg7Ser)	HSPB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
450280	NM_002180.3(IGHMBP2):c.1766G>T (p.Gly589Val)	IGHMBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1019333	NM_006308.3(HSPB3):c.2T>C (p.Met1Thr)	HSPB3	Uncertain significance	criteria provided, single submitter
1162971	NM_006308.3(HSPB3):c.43C>T (p.Arg15Cys)	HSPB3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1359519	NM_006308.3(HSPB3):c.37C>T (p.Pro13Ser)	HSPB3	Uncertain significance	criteria provided, single submitter
1472112	NM_006308.3(HSPB3):c.275G>A (p.Gly92Asp)	HSPB3	Uncertain significance	criteria provided, single submitter
1508343	NM_006308.3(HSPB3):c.322G>A (p.Gly108Ser)	HSPB3	Uncertain significance	criteria provided, single submitter
2037449	NM_006308.3(HSPB3):c.25C>T (p.Leu9Phe)	HSPB3	Uncertain significance	criteria provided, single submitter
2173772	NM_006308.3(HSPB3):c.209A>G (p.His70Arg)	HSPB3	Uncertain significance	criteria provided, single submitter
2193273	NM_006308.3(HSPB3):c.127G>A (p.Val43Met)	HSPB3	Uncertain significance	criteria provided, single submitter
2425565	NC_000005.9:g.(?53751620)(53752072_?)dup	HSPB3	Uncertain significance	criteria provided, single submitter
2724293	NM_006308.3(HSPB3):c.176C>T (p.Ala59Val)	HSPB3	Uncertain significance	criteria provided, single submitter
2738849	NM_006308.3(HSPB3):c.408T>C (p.Asp136=)	HSPB3	Uncertain significance	criteria provided, single submitter
2906176	NM_006308.3(HSPB3):c.224T>A (p.Leu75Gln)	HSPB3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2907790	NM_006308.3(HSPB3):c.92A>G (p.Asp31Gly)	HSPB3	Uncertain significance	criteria provided, single submitter
2910188	NM_006308.3(HSPB3):c.185C>T (p.Thr62Met)	HSPB3	Uncertain significance	criteria provided, single submitter
353896	NM_006308.3(HSPB3):c.-89T>C	HSPB3	Uncertain significance	criteria provided, single submitter
353897	NM_006308.3(HSPB3):c.158C>A (p.Ser53Tyr)	HSPB3	Uncertain significance	criteria provided, single submitter
353904	NM_006308.3(HSPB3):c.*16T>G	HSPB3	Uncertain significance	criteria provided, single submitter
3627678	NM_006308.3(HSPB3):c.44G>T (p.Arg15Leu)	HSPB3	Uncertain significance	criteria provided, single submitter
3642136	NM_006308.3(HSPB3):c.155A>G (p.Gln52Arg)	HSPB3	Uncertain significance	criteria provided, single submitter
3711544	NM_006308.3(HSPB3):c.126C>G (p.Ile42Met)	HSPB3	Uncertain significance	criteria provided, single submitter
4056768	NM_006308.3(HSPB3):c.421G>A (p.Val141Met)	HSPB3	Uncertain significance	criteria provided, single submitter
471412	NM_006308.3(HSPB3):c.194G>A (p.Arg65Gln)	HSPB3	Uncertain significance	criteria provided, single submitter
4738751	NM_006308.3(HSPB3):c.227A>T (p.Asp76Val)	HSPB3	Uncertain significance	criteria provided, single submitter
4741504	NM_006308.3(HSPB3):c.191C>T (p.Pro64Leu)	HSPB3	Uncertain significance	criteria provided, single submitter
4743954	NM_006308.3(HSPB3):c.44G>A (p.Arg15His)	HSPB3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
HSPB3	Supportive	Autosomal dominant	distal hereditary motor neuropathy type 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HSPB3	Orphanet:139525	Distal hereditary motor neuropathy type 2
IGHMBP2	Orphanet:443073	Charcot-Marie-Tooth disease type 2S
IGHMBP2	Orphanet:98920	Spinal muscular atrophy with respiratory distress type 1

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
HSPB3	HGNC:5248	ENSG00000169271	Q12988	Heat shock protein beta-3	gencc,clinvar
IGHMBP2	HGNC:5542	ENSG00000132740	P38935	DNA-binding protein SMUBP-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HSPB3	Heat shock protein beta-3	Inhibitor of actin polymerization.
IGHMBP2	DNA-binding protein SMUBP-2	5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HSPB3	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
IGHMBP2	Transcription factor	no	3.6.4.12	Znf_AN1, R3H_dom, AAA+_ATPase

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
heart right ventricle	1
left ventricle myocardium	1
myocardium	1
esophagogastric junction muscularis propria	1
lower esophagus muscularis layer	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HSPB3	189	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
IGHMBP2	189	ubiquitous	yes	mucosa of stomach, esophagogastric junction muscularis propria, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPB3	2,711
IGHMBP2	1,265

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IGHMBP2	P38935	4
HSPB3	Q12988	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
response to unfolded protein	1	300.9×	0.003	HSPB3

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
HSPB3	0	0
IGHMBP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IGHMBP2	3.6.4.12	DNA helicase

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	0
E	Difficult family or no structure, no drug	2	HSPB3, IGHMBP2

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)
HSPB3	0	—
IGHMBP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.