adult-onset distal myopathy due to VCP mutation

Summary

adult-onset distal myopathy due to VCP mutation (MONDO:0018006) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0002460	Distal muscle weakness	Very frequent (80-99%)
HP:0000726	Dementia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001437	Abnormality of the musculature of the lower limbs	Frequent (30-79%)
HP:0002344	Progressive neurologic deterioration	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002380	Fasciculations	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003691	Scapular winging	Frequent (30-79%)
HP:0003805	Rimmed vacuoles	Frequent (30-79%)
HP:0008180	Mildly elevated creatine kinase	Frequent (30-79%)
HP:0008954	Intrinsic hand muscle atrophy	Frequent (30-79%)
HP:0008978	Necrotizing myopathy	Frequent (30-79%)
HP:0009005	Weakness of the intrinsic hand muscles	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0012548	Fatty replacement of skeletal muscle	Frequent (30-79%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001349	Facial diplegia	Occasional (5-29%)
HP:0002607	Bowel incontinence	Occasional (5-29%)
HP:0003418	Back pain	Occasional (5-29%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000762	Decreased nerve conduction velocity	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Excluded (0%)
HP:0003701	Proximal muscle weakness	Excluded (0%)
HP:0002792	Reduced vital capacity	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	adult-onset distal myopathy due to VCP mutation
Mondo ID	MONDO:0018006
Orphanet	329478
UMLS	C4749506
MedGen	1660404
GARD	0021492
Is cancer (heuristic)	no

Data availability: 1 GenCC gene-disease record · 55 cell lines.

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 › autosomal dominant distal myopathy › adult-onset distal myopathy due to VCP mutation

Related subtypes (14): tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure, distal myopathy, Welander type, myofibrillar myopathy 2, myofibrillar myopathy 3, myofibrillar myopathy 4, Finnish upper limb-onset distal myopathy, distal myopathy with posterior leg and anterior hand involvement, distal myopathy, Tateyama type, KLHL9-related early-onset distal myopathy, distal myopathy with vocal cord weakness, TARDBP-related predominantly upper-limb distal myopathy, asymetric thumb-handgrip weakness-distal myopathy, calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy

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

No tiered GWAS variants or ClinVar records for this disease.

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	Definitive	Autosomal dominant	inclusion body myopathy with Paget disease of bone and frontotemporal dementia	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

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: 0.