neuronopathy, distal hereditary motor, type 2B

Summary

neuronopathy, distal hereditary motor, type 2B (MONDO:0012080) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 52

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, type 2B
Mondo ID	MONDO:0012080
MeSH	C567084
OMIM	608634
DOID	DOID:0111207
UMLS	C2608087
MedGen	382017
GARD	0018263
Is cancer (heuristic)	no

Also known as: HMN2B · HSPB1 neuronopathy, distal hereditary motor · neuronopathy, distal hereditary motor caused by mutation in HSPB1 · neuronopathy, distal hereditary motor, type IIB

Data availability: 52 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 dominant disease › neuronopathy, distal hereditary motor, autosomal dominant › distal hereditary motor neuropathy type 2 › neuronopathy, distal hereditary motor, type 2B

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

52 retrieved; paginated sample, class counts are floors:

12 conflicting classifications of pathogenicity, 10 uncertain significance, 9 benign/likely benign, 9 pathogenic/likely pathogenic, 6 pathogenic, 4 benign, 1 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4221	NM_024301.5(FKRP):c.826C>A (p.Leu276Ile)	FKRP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217230	NM_001540.5(HSPB1):c.407G>T (p.Arg136Leu)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
220419	NM_001540.5(HSPB1):c.250G>C (p.Gly84Arg)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
423339	NM_001540.5(HSPB1):c.180dup (p.Ala61fs)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
533814	NM_001540.5(HSPB1):c.116C>T (p.Pro39Leu)	HSPB1	Pathogenic	criteria provided, multiple submitters, no conflicts
632006	NM_001540.5(HSPB1):c.250G>A (p.Gly84Arg)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637060	NM_001540.5(HSPB1):c.404C>G (p.Ser135Cys)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7478	NM_001540.5(HSPB1):c.404C>T (p.Ser135Phe)	HSPB1	Pathogenic	criteria provided, multiple submitters, no conflicts
7479	NM_001540.5(HSPB1):c.379C>T (p.Arg127Trp)	HSPB1	Pathogenic	criteria provided, multiple submitters, no conflicts
7480	NM_001540.5(HSPB1):c.452C>T (p.Thr151Ile)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7481	NM_001540.5(HSPB1):c.545C>T (p.Pro182Leu)	HSPB1	Pathogenic	criteria provided, single submitter
7483	NM_001540.5(HSPB1):c.544C>T (p.Pro182Ser)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7484	NM_001540.5(HSPB1):c.418C>G (p.Arg140Gly)	HSPB1	Pathogenic	criteria provided, multiple submitters, no conflicts
7485	NM_001540.5(HSPB1):c.295C>A (p.Leu99Met)	HSPB1	Pathogenic	no assertion criteria provided
954704	NM_001540.5(HSPB1):c.510del (p.Lys171fs)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3896881	NM_001540.5(HSPB1):c.109dup (p.Arg37fs)	HSPB1	Likely pathogenic	criteria provided, single submitter
216545	NM_001540.5(HSPB1):c.610G>A (p.Ala204Thr)	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360734	NM_001540.3(HSPB1):c.-122G>T	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360736	NM_001540.5(HSPB1):c.-4C>T	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360737	NM_001540.5(HSPB1):c.216C>T (p.Ala72=)	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360738	NM_001540.5(HSPB1):c.383A>G (p.Gln128Arg)	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
447529	NM_001540.5(HSPB1):c.364+6C>G	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533816	NM_001540.5(HSPB1):c.365-6C>G	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
549674	NM_001540.5(HSPB1):c.415A>G (p.Thr139Ala)	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
560407	NM_001540.5(HSPB1):c.19C>T (p.Pro7Ser)	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
560408	NM_001540.5(HSPB1):c.158G>A (p.Gly53Asp)	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
560409	NM_001540.5(HSPB1):c.560C>T (p.Ser187Leu)	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
681059	NM_001540.5(HSPB1):c.210G>A (p.Ala70=)	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001251	NM_001540.5(HSPB1):c.253G>T (p.Val85Phe)	HSPB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382865	NM_001540.5(HSPB1):c.401T>C (p.Ile134Thr)	HSPB1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 8 · 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
HSPB1	Moderate	Autosomal dominant	neuronopathy, distal hereditary motor, type 2B	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HSPB1	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB1	Orphanet:99940	Autosomal dominant Charcot-Marie-Tooth disease type 2F
FKRP	Orphanet:34515	FKRP-related limb-girdle muscular dystrophy R9
FKRP	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
FKRP	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
FKRP	Orphanet:370980	Congenital muscular dystrophy without intellectual disability
FKRP	Orphanet:588	Muscle-eye-brain disease
FKRP	Orphanet:899	Walker-Warburg syndrome

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
HSPB1	HGNC:5246	ENSG00000106211	P04792	Heat shock protein beta-1	gencc,clinvar
FKRP	HGNC:17997	ENSG00000181027	Q9H9S5	Ribitol 5-phosphate transferase FKRP	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HSPB1	Heat shock protein beta-1	Small heat shock protein which functions as a molecular chaperone probably maintaining denatured proteins in a folding-competent state.
FKRP	Ribitol 5-phosphate transferase FKRP	Catalyzes the transfer of a ribitol 5-phosphate from CDP-L-ribitol to the ribitol 5-phosphate previously attached by FKTN/fukutin to the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine-beta-4-(phos…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HSPB1	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
FKRP	Other/Unknown	no		LicD/FKTN/FKRP_NTP_transf, LicD_transferase, FKRP_N

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
ascending aorta	1
lower esophagus mucosa	1
thoracic aorta	1
cardiac muscle of right atrium	1
hindlimb stylopod muscle	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HSPB1	299	ubiquitous	marker	lower esophagus mucosa, ascending aorta, thoracic aorta
FKRP	230	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPB1	5,491
FKRP	1,436

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FKRP	Q9H9S5	8
HSPB1	P04792	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Matriglycan biosynthesis on DAG1	1	407.9×	0.014	FKRP
Attenuation phase	1	203.9×	0.014	HSPB1
HSF1 activation	1	190.3×	0.014	HSPB1
HSF1-dependent transactivation	1	158.6×	0.014	HSPB1
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	124.1×	0.014	HSPB1
Extra-nuclear estrogen signaling	1	85.2×	0.015	HSPB1
Regulation of HSF1-mediated heat shock response	1	69.6×	0.015	HSPB1
VEGFA-VEGFR2 Pathway	1	69.6×	0.015	HSPB1
MAPK6/MAPK4 signaling	1	68.0×	0.015	HSPB1

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
pentitol metabolic process	1	8426.0×	0.002	FKRP
filtration diaphragm assembly	1	8426.0×	0.002	FKRP
negative regulation of protein kinase C signaling	1	8426.0×	0.002	HSPB1
pentose metabolic process	1	4213.0×	0.004	FKRP
creatine metabolic process	1	2106.5×	0.004	FKRP
connective tissue development	1	2106.5×	0.004	FKRP
oxygen metabolic process	1	2106.5×	0.004	FKRP
maintenance of protein localization in endoplasmic reticulum	1	1685.2×	0.004	FKRP
localization of cell	1	1404.3×	0.005	FKRP
connective tissue replacement	1	1203.7×	0.005	FKRP
anterograde axonal protein transport	1	1053.2×	0.005	HSPB1
diaphragm development	1	936.2×	0.005	FKRP
intestinal epithelial structure maintenance	1	936.2×	0.005	HSPB1
protein import	1	842.6×	0.005	FKRP
skeletal muscle fiber differentiation	1	842.6×	0.005	FKRP
response to alcohol	1	766.0×	0.005	FKRP
reelin-mediated signaling pathway	1	601.9×	0.006	FKRP
regulation of protein phosphorylation	1	561.7×	0.006	HSPB1
positive regulation of endothelial cell chemotaxis	1	495.6×	0.006	HSPB1
respiratory system process	1	468.1×	0.006	FKRP
protein O-linked glycosylation via mannose	1	468.1×	0.006	FKRP
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	468.1×	0.006	HSPB1
glial cell differentiation	1	443.5×	0.006	FKRP
skeletal muscle tissue regeneration	1	443.5×	0.006	FKRP
protein refolding	1	312.1×	0.007	HSPB1
protein tetramerization	1	312.1×	0.007	FKRP
cellular response to vascular endothelial growth factor stimulus	1	280.9×	0.008	HSPB1
neuromuscular process	1	263.3×	0.008	FKRP
basement membrane organization	1	255.3×	0.008	FKRP
adult walking behavior	1	247.8×	0.008	FKRP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HSPB1	1	2
FKRP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DORAMAPIMOD	2	HSPB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HSPB1	70	Binding:70

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
DORAMAPIMOD	2	HSPB1

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	1	HSPB1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FKRP

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)
FKRP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.