Charcot-Marie-Tooth disease axonal type 2F

Summary

Charcot-Marie-Tooth disease axonal type 2F (MONDO:0011687) is a disease caused by HSPB1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HSPB1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 329
• Phenotypes (HPO): 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0001315	Reduced tendon reflexes	Very frequent (80-99%)
HP:0001762	Talipes equinovarus	Very frequent (80-99%)
HP:0003376	Steppage gait	Very frequent (80-99%)
HP:0003444	EMG: chronic denervation signs	Very frequent (80-99%)
HP:0003445	EMG: neuropathic changes	Very frequent (80-99%)
HP:0003477	Peripheral axonal neuropathy	Very frequent (80-99%)
HP:0007289	Limb fasciculations	Very frequent (80-99%)
HP:0007328	Impaired pain sensation	Very frequent (80-99%)
HP:0007340	Lower limb muscle weakness	Very frequent (80-99%)
HP:0008944	Distal lower limb amyotrophy	Very frequent (80-99%)
HP:0009129	Upper limb amyotrophy	Very frequent (80-99%)
HP:0010829	Impaired temperature sensition	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2F
Mondo ID	MONDO:0011687
MeSH	C535413
OMIM	606595
Orphanet	99940
DOID	DOID:0110163
SNOMED CT	719510006
UMLS	C1847823
MedGen	335784
GARD	0009194
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2F · Charcot Marie Tooth disease type 2F · Charcot-Marie-Tooth disease type 2 caused by mutation in HSPB1 · Charcot-Marie-Tooth disease type 2F · Charcot-Marie-Tooth disease, axonal, type 2F · Charcot-Marie-Tooth disease, neuronal, type 2F · Charcot-Marie-Tooth neuropathy, type 2F · CMT 2F · CMT2F · HSPB1 Charcot-Marie-Tooth disease type 2

Data availability: 329 ClinVar variants · 5 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 2F

Related subtypes (37): Charcot-Marie-Tooth disease type 2A1, Charcot-Marie-Tooth disease type 2B, Charcot-Marie-Tooth disease type 2D, Charcot-Marie-Tooth disease type 2B1, Charcot-Marie-Tooth disease type 2B2, Charcot-Marie-Tooth disease axonal type 2C, Charcot-Marie-Tooth disease type 2I, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease axonal type 2H, Charcot-Marie-Tooth disease type 2J, Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease axonal type 2L, Charcot-Marie-Tooth disease type 2A2, giant axonal neuropathy 2, Charcot-Marie-Tooth disease axonal type 2N, Charcot-Marie-Tooth disease axonal type 2O, Charcot-Marie-Tooth disease axonal type 2P, Charcot-Marie-Tooth disease axonal type 2Q, Charcot-Marie-Tooth disease type 2R, Charcot-Marie-Tooth disease axonal type 2S, Charcot-Marie-Tooth disease axonal type 2U, Charcot-Marie-Tooth disease axonal type 2V, autosomal dominant Charcot-Marie-Tooth disease type 2W, Charcot-Marie-Tooth disease axonal type 2X, Charcot-Marie-Tooth disease type 2Y, Charcot-Marie-Tooth disease axonal type 2Z, Charcot-Marie-Tooth disease axonal type 2CC, autosomal dominant Charcot-Marie-Tooth disease type 2M, Charcot-Marie-Tooth disease type 2B5, autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation, autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation, autosomal dominant Charcot-Marie-Tooth disease type 2K, Charcot-Marie-Tooth disease, axonal, type 2EE, autosomal dominant charcot-marie-tooth disease type 2 due to DGAT2 mutation, Charcot-Marie-Tooth disease type 2T, MME-related autosomal dominant Charcot Marie Tooth disease type 2, Charcot-Marie-tooth disease, axonal, type 2DD

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

329 retrieved; paginated sample, class counts are floors:

170 uncertain significance, 76 likely benign, 28 conflicting classifications of pathogenicity, 15 pathogenic/likely pathogenic, 15 benign/likely benign, 14 pathogenic, 6 likely pathogenic, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1455479	NC_000007.13:g.(?75933099)(75933490_?)del	HSPB1	Pathogenic	criteria provided, single submitter
157529	NM_001540.5(HSPB1):c.380G>T (p.Arg127Leu)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1930599	NM_001540.5(HSPB1):c.245_246insT (p.Ser83fs)	HSPB1	Pathogenic	criteria provided, single submitter
2035012	NM_001540.5(HSPB1):c.472del (p.Ser158fs)	HSPB1	Pathogenic	criteria provided, single submitter
217230	NM_001540.5(HSPB1):c.407G>T (p.Arg136Leu)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217231	NM_001540.5(HSPB1):c.523C>T (p.Gln175Ter)	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
410713	NM_001540.5(HSPB1):c.522_523delinsCT (p.Gln175Ter)	HSPB1	Pathogenic	criteria provided, single submitter
421350	NM_001540.5(HSPB1):c.416C>T (p.Thr139Met)	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
439794	NM_001540.5(HSPB1):c.512del (p.Lys171fs)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447531	NM_001540.5(HSPB1):c.539C>T (p.Thr180Ile)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
533813	NM_001540.5(HSPB1):c.404C>A (p.Ser135Tyr)	HSPB1	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
584236	NC_000007.14:g.(?76303802)(76304173_?)del	HSPB1	Pathogenic	criteria provided, single submitter
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
637688	NM_001540.5(HSPB1):c.476_477del (p.Pro159fs)	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
7482	NM_001540.5(HSPB1):c.406C>T (p.Arg136Trp)	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
810107	NM_001540.5(HSPB1):c.407G>A (p.Arg136Gln)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
831819	NC_000007.14:g.(?76303789)(76304183_?)del	HSPB1	Pathogenic	criteria provided, single submitter
946496	NM_001540.5(HSPB1):c.544C>G (p.Pro182Ala)	HSPB1	Pathogenic	criteria provided, multiple submitters, no conflicts
954704	NM_001540.5(HSPB1):c.510del (p.Lys171fs)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2884503	NM_001540.5(HSPB1):c.116C>G (p.Pro39Arg)	HSPB1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2F	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

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
HSPB1	HGNC:5246	ENSG00000106211	P04792	Heat shock protein beta-1	gencc,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.

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)
HSPB1	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
ascending aorta	1
lower esophagus mucosa	1
thoracic aorta	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPB1	5,491

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HSPB1	P04792	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Attenuation phase	1	407.9×	0.007	HSPB1
HSF1 activation	1	380.7×	0.007	HSPB1
HSF1-dependent transactivation	1	317.2×	0.007	HSPB1
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	248.3×	0.007	HSPB1
Extra-nuclear estrogen signaling	1	170.4×	0.007	HSPB1
Regulation of HSF1-mediated heat shock response	1	139.3×	0.007	HSPB1
VEGFA-VEGFR2 Pathway	1	139.3×	0.007	HSPB1
MAPK6/MAPK4 signaling	1	135.9×	0.007	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of protein kinase C signaling	1	16852.0×	0.001	HSPB1
anterograde axonal protein transport	1	2106.5×	0.004	HSPB1
intestinal epithelial structure maintenance	1	1872.4×	0.004	HSPB1
regulation of protein phosphorylation	1	1123.5×	0.004	HSPB1
positive regulation of endothelial cell chemotaxis	1	991.3×	0.004	HSPB1
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	936.2×	0.004	HSPB1
protein refolding	1	624.1×	0.004	HSPB1
cellular response to vascular endothelial growth factor stimulus	1	561.7×	0.004	HSPB1
regulation of canonical NF-kappaB signal transduction	1	481.5×	0.004	HSPB1
vascular endothelial growth factor receptor signaling pathway	1	481.5×	0.004	HSPB1
regulation of translational initiation	1	468.1×	0.004	HSPB1
response to heat	1	421.3×	0.005	HSPB1
positive regulation of blood vessel endothelial cell migration	1	391.9×	0.005	HSPB1
platelet aggregation	1	337.0×	0.005	HSPB1
response to unfolded protein	1	300.9×	0.005	HSPB1
positive regulation of interleukin-1 beta production	1	259.3×	0.006	HSPB1
regulation of autophagy	1	240.7×	0.006	HSPB1
positive regulation of tumor necrosis factor production	1	153.2×	0.008	HSPB1
response to virus	1	144.0×	0.008	HSPB1
positive regulation of angiogenesis	1	115.4×	0.010	HSPB1
protein folding	1	103.4×	0.011	HSPB1
intracellular signal transduction	1	38.1×	0.027	HSPB1
negative regulation of apoptotic process	1	34.8×	0.029	HSPB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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: 1; 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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.