Charcot-Marie-Tooth disease type 2Y

Summary

Charcot-Marie-Tooth disease type 2Y (MONDO:0014735) is a disease caused by VCP (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VCP (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 11
• Phenotypes (HPO): 43
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

43 HPO clinical features (Orphanet curated; top 43 by frequency):

HPO ID	Term	Frequency
HP:0000762	Decreased nerve conduction velocity	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002141	Gait imbalance	Frequent (30-79%)
HP:0002166	Impaired vibration sensation in the lower limbs	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002936	Distal sensory impairment	Frequent (30-79%)
HP:0003438	Absent Achilles reflex	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0007010	Poor fine motor coordination	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0008959	Distal upper limb muscle weakness	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0009046	Difficulty running	Frequent (30-79%)
HP:0009130	Hand muscle atrophy	Frequent (30-79%)
HP:0010830	Impaired tactile sensation	Frequent (30-79%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001315	Reduced tendon reflexes	Occasional (5-29%)
HP:0001765	Hammertoe	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002136	Broad-based gait	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002359	Frequent falls	Occasional (5-29%)
HP:0002938	Lumbar hyperlordosis	Occasional (5-29%)
HP:0003236	Elevated circulating creatine kinase concentration	Occasional (5-29%)
HP:0003376	Steppage gait	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003401	Paresthesia	Occasional (5-29%)
HP:0003551	Difficulty climbing stairs	Occasional (5-29%)
HP:0003691	Scapular winging	Occasional (5-29%)
HP:0003701	Proximal muscle weakness	Occasional (5-29%)
HP:0003731	Quadriceps muscle weakness	Occasional (5-29%)
HP:0006389	Limited knee flexion	Occasional (5-29%)
HP:0006886	Impaired distal vibration sensation	Occasional (5-29%)
HP:0006944	Abolished vibration sense	Occasional (5-29%)
HP:0007328	Impaired pain sensation	Occasional (5-29%)
HP:0008994	Proximal muscle weakness in lower limbs	Occasional (5-29%)
HP:0008997	Proximal muscle weakness in upper limbs	Occasional (5-29%)
HP:0009053	Distal lower limb muscle weakness	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 2Y
Mondo ID	MONDO:0014735
OMIM	616687
Orphanet	435387
DOID	DOID:0110168
NCIT	C168974
UMLS	C5569026
MedGen	1800449
GARD	0017714
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2 due to VCP mutation · Charcot-Marie-Tooth disease type 2 caused by mutation in VCP · Charcot-Marie-Tooth disease, axonal, type 2y · Charcot-Marie-Tooth disease, type 2Y · CMT2 due to VCP mutation · CMT2Y · VCP Charcot-Marie-Tooth disease type 2

Data availability: 11 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

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 type 2Y

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 axonal type 2F, 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 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

11 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
218306	NM_007126.5(VCP):c.290G>A (p.Gly97Glu)	VCP	Pathogenic	criteria provided, single submitter
3768936	NM_007126.5(VCP):c.410C>T (p.Pro137Leu)	VCP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8473	NM_007126.5(VCP):c.572G>A (p.Arg191Gln)	VCP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218305	NM_007126.5(VCP):c.553G>A (p.Glu185Lys)	VCP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582679	NM_007126.5(VCP):c.766C>G (p.Arg256Gly)	VCP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
963526	NM_007126.5(VCP):c.1106T>C (p.Ile369Thr)	VCP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2442076	NM_007126.5(VCP):c.961G>A (p.Glu321Lys)	VCP	Uncertain significance	criteria provided, single submitter
260121	NM_007126.5(VCP):c.129+47G>A	VCP	Benign	criteria provided, multiple submitters, no conflicts
260123	NM_007126.5(VCP):c.1360-35A>G	VCP	Benign	criteria provided, multiple submitters, no conflicts
260124	NM_007126.5(VCP):c.1695+8A>G	VCP	Benign	criteria provided, multiple submitters, no conflicts
260128	NM_007126.5(VCP):c.811+3G>A	VCP	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
VCP	Strong	Autosomal dominant	Charcot-Marie-Tooth disease type 2Y	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VCP	Orphanet:100070	Progressive non-fluent aphasia
VCP	Orphanet:275864	Behavioral variant of frontotemporal dementia
VCP	Orphanet:275872	Frontotemporal dementia with motor neuron disease
VCP	Orphanet:329475	Spastic paraplegia-Paget disease of bone syndrome
VCP	Orphanet:329478	Adult-onset distal myopathy due to VCP mutation
VCP	Orphanet:435387	Autosomal dominant Charcot-Marie-Tooth disease type 2Y
VCP	Orphanet:52430	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
VCP	Orphanet:803	Amyotrophic lateral sclerosis

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
VCP	HGNC:12666	ENSG00000165280	P55072	Transitional endoplasmic reticulum ATPase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VCP	Transitional endoplasmic reticulum ATPase	Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VCP	Enzyme (other)	yes	3.6.4.6	CDC4_N-term_subdom, AAA+_ATPase, ATPase_AAA_core

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
adrenal tissue	1
islet of Langerhans	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VCP	294	ubiquitous	marker	stromal cell of endometrium, adrenal tissue, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VCP	10,015

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VCP	P55072	144

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 55. 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
Attachment and Entry	1	2855.0×	0.008	VCP
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1	2284.0×	0.008	VCP
DNA Damage Bypass	1	2284.0×	0.008	VCP
Hh mutants abrogate ligand secretion	1	1427.5×	0.009	VCP
Early SARS-CoV-2 Infection Events	1	1038.2×	0.009	VCP
Josephin domain DUBs	1	951.7×	0.009	VCP
Protein ubiquitination	1	815.7×	0.009	VCP
Protein methylation	1	671.8×	0.009	VCP
Translesion Synthesis by POLH	1	601.0×	0.009	VCP
Attachment and Entry	1	601.0×	0.009	VCP
ABC transporter disorders	1	439.2×	0.010	VCP
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	423.0×	0.010	VCP
Cellular response to heat stress	1	393.8×	0.010	VCP
HSF1 activation	1	380.7×	0.010	VCP
Dengue Virus Genome Translation and Replication	1	317.2×	0.011	VCP
RHOH GTPase cycle	1	308.6×	0.011	VCP
Ovarian tumor domain proteases	1	278.5×	0.011	VCP
Selective autophagy	1	278.5×	0.011	VCP
Aggrephagy	1	248.3×	0.011	VCP
Hh mutants are degraded by ERAD	1	243.0×	0.011	VCP
Defective CFTR causes cystic fibrosis	1	219.6×	0.012	VCP
Hedgehog ligand biogenesis	1	211.5×	0.012	VCP
E3 ubiquitin ligases ubiquitinate target proteins	1	193.6×	0.012	VCP
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	193.6×	0.012	VCP
Signaling by Hedgehog	1	184.2×	0.012	VCP
Autophagy	1	148.3×	0.014	VCP
SARS-CoV-1 Infection	1	142.8×	0.014	VCP
Cellular response to chemical stress	1	142.8×	0.014	VCP
Disorders of transmembrane transporters	1	139.3×	0.014	VCP
Deubiquitination	1	124.1×	0.014	VCP

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
flavin adenine dinucleotide catabolic process	1	16852.0×	0.001	VCP
endoplasmic reticulum stress-induced pre-emptive quality control	1	8426.0×	0.001	VCP
positive regulation of protein K63-linked deubiquitination	1	8426.0×	0.001	VCP
mitotic spindle disassembly	1	5617.3×	0.001	VCP
cytoplasm protein quality control	1	5617.3×	0.001	VCP
cellular response to arsenite ion	1	5617.3×	0.001	VCP
positive regulation of oxidative phosphorylation	1	5617.3×	0.001	VCP
regulation of protein localization to chromatin	1	5617.3×	0.001	VCP
endosome to lysosome transport via multivesicular body sorting pathway	1	2808.7×	0.002	VCP
aggresome assembly	1	2808.7×	0.002	VCP
stress granule disassembly	1	2407.4×	0.002	VCP
positive regulation of mitochondrial membrane potential	1	2106.5×	0.002	VCP
regulation of aerobic respiration	1	2106.5×	0.002	VCP
NAD+ metabolic process	1	1872.4×	0.002	VCP
protein-DNA covalent cross-linking repair	1	1685.2×	0.002	VCP
negative regulation of protein localization to chromatin	1	1532.0×	0.002	VCP
cellular response to misfolded protein	1	1404.3×	0.002	VCP
positive regulation of ATP biosynthetic process	1	1203.7×	0.002	VCP
viral genome replication	1	1123.5×	0.002	VCP
retrograde protein transport, ER to cytosol	1	991.3×	0.002	VCP
translesion synthesis	1	936.2×	0.002	VCP
proteasomal protein catabolic process	1	766.0×	0.003	VCP
negative regulation of hippo signaling	1	702.2×	0.003	VCP
regulation of synapse organization	1	648.1×	0.003	VCP
ATP metabolic process	1	468.1×	0.004	VCP
negative regulation of smoothened signaling pathway	1	455.5×	0.004	VCP
interstrand cross-link repair	1	432.1×	0.004	VCP
establishment of protein localization	1	432.1×	0.004	VCP
autophagosome maturation	1	351.1×	0.004	VCP
cellular response to heat	1	343.9×	0.004	VCP

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
VCP	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VCP	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	VCP
GANCICLOVIR	4	VCP
HEXACHLOROPHENE	4	VCP
CB-5083	1	VCP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VCP	120	Binding:120

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
VCP	3.6.4.6	vesicle-fusing ATPase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
VCP	120

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

4 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)
CLOTRIMAZOLE	4	VCP
GANCICLOVIR	4	VCP
HEXACHLOROPHENE	4	VCP
CB-5083	1	VCP

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	VCP
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	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: 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