Charcot-Marie-Tooth disease axonal type 2L

disease

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Also known as autosomal dominant Charcot-Marie-Tooth disease type 2LCharcot-Marie-Tooth disease type 2 caused by mutation in HSPB8Charcot-Marie-Tooth disease type 2LCharcot-Marie-Tooth disease, axonal, type 2LCMT2LHSPB8 Charcot-Marie-Tooth disease type 2

Summary

Charcot-Marie-Tooth disease axonal type 2L (MONDO:0012096) is a disease caused by HSPB8 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: HSPB8 (GenCC Strong)
Cohort genes: 1
ClinVar variants: 219
Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2L
Mondo ID	MONDO:0012096
OMIM	608673
Orphanet	99945
DOID	DOID:0110174
SNOMED CT	719513008
UMLS	C1837552
MedGen	324826
GARD	0012432
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2L · Charcot-Marie-Tooth disease type 2 caused by mutation in HSPB8 · Charcot-Marie-Tooth disease type 2L · Charcot-Marie-Tooth disease, axonal, type 2L · CMT2L · HSPB8 Charcot-Marie-Tooth disease type 2

Data availability: 219 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease type 2 › Charcot-Marie-Tooth disease axonal type 2L

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

219 retrieved; paginated sample, class counts are floors:

133 uncertain significance, 53 likely benign, 13 benign, 7 benign/likely benign, 7 conflicting classifications of pathogenicity, 5 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1709856	NM_014365.3(HSPB8):c.508_509del (p.Gln170fs)	HSPB8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805628	NM_014365.3(HSPB8):c.508del (p.Gln170fs)	HSPB8	Pathogenic	criteria provided, single submitter
2618	NM_014365.3(HSPB8):c.421A>G (p.Lys141Glu)	HSPB8	Pathogenic	criteria provided, multiple submitters, no conflicts
2619	NM_014365.3(HSPB8):c.423G>T (p.Lys141Asn)	HSPB8	Pathogenic	criteria provided, single submitter
560412	NM_014365.3(HSPB8):c.422A>T (p.Lys141Met)	HSPB8	Pathogenic	criteria provided, single submitter
972979	NM_014365.3(HSPB8):c.577_580dup (p.Thr194fs)	HSPB8	Pathogenic	no assertion criteria provided
464509	NM_014365.3(HSPB8):c.266C>A (p.Pro89Gln)	HSPB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464510	NM_014365.3(HSPB8):c.432-10T>A	HSPB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533139	NM_014365.3(HSPB8):c.503C>T (p.Ala168Val)	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
637689	NM_014365.3(HSPB8):c.422A>C (p.Lys141Thr)	HSPB8	Conflicting classifications of pathogenicity	no assertion criteria provided
855097	NM_014365.3(HSPB8):c.114C>A (p.Asp38Glu)	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
1006960	NM_014365.3(HSPB8):c.461T>C (p.Val154Ala)	HSPB8	Uncertain significance	criteria provided, single submitter
1007967	NC_000012.11:g.(?119631494)(119631673_?)dup	HSPB8	Uncertain significance	criteria provided, single submitter
1014121	NM_014365.3(HSPB8):c.188C>T (p.Thr63Ile)	HSPB8	Uncertain significance	criteria provided, single submitter
1019441	NM_014365.3(HSPB8):c.49C>T (p.Arg17Cys)	HSPB8	Uncertain significance	criteria provided, single submitter
1020904	NM_014365.3(HSPB8):c.149A>T (p.Asp50Val)	HSPB8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1048978	NM_014365.3(HSPB8):c.17T>C (p.Met6Thr)	HSPB8	Uncertain significance	criteria provided, single submitter
1054940	NM_014365.3(HSPB8):c.134C>G (p.Thr45Arg)	HSPB8	Uncertain significance	criteria provided, single submitter
1055000	NM_014365.3(HSPB8):c.365C>A (p.Ser122Tyr)	HSPB8	Uncertain significance	criteria provided, single submitter
1055783	NM_014365.3(HSPB8):c.563dup (p.Asp189fs)	HSPB8	Uncertain significance	criteria provided, single submitter
1351461	NM_014365.3(HSPB8):c.58C>T (p.Pro20Ser)	HSPB8	Uncertain significance	criteria provided, single submitter
1356495	NM_014365.3(HSPB8):c.44G>A (p.Arg15His)	HSPB8	Uncertain significance	criteria provided, single submitter
1359615	NM_014365.3(HSPB8):c.479C>T (p.Pro160Leu)	HSPB8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1365464	NM_014365.3(HSPB8):c.451C>T (p.Pro151Ser)	HSPB8	Uncertain significance	criteria provided, single submitter
1365569	NM_014365.3(HSPB8):c.150C>A (p.Asp50Glu)	HSPB8	Uncertain significance	criteria provided, single submitter
1368257	NM_014365.3(HSPB8):c.142T>C (p.Trp48Arg)	HSPB8	Uncertain significance	criteria provided, single submitter
1385402	NM_014365.3(HSPB8):c.391G>A (p.Glu131Lys)	HSPB8	Uncertain significance	criteria provided, single submitter
1388452	NM_014365.3(HSPB8):c.212G>A (p.Arg71Gln)	HSPB8	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
HSPB8	Strong	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2L	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

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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease

Cohort genes: HSPB8