Cap myopathy

Summary

Cap myopathy (MONDO:0015753) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 1
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	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:0000218	High palate	Frequent (30-79%)
HP:0000276	Long face	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0004303	Abnormal muscle fiber morphology	Frequent (30-79%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001611	Hypernasal speech	Occasional (5-29%)
HP:0001634	Mitral valve prolapse	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0002359	Frequent falls	Occasional (5-29%)
HP:0002421	Poor head control	Occasional (5-29%)
HP:0002616	Aortic root aneurysm	Occasional (5-29%)
HP:0002938	Lumbar hyperlordosis	Occasional (5-29%)
HP:0002943	Thoracic scoliosis	Occasional (5-29%)
HP:0003388	Easy fatigability	Occasional (5-29%)
HP:0003391	Gowers sign	Occasional (5-29%)
HP:0003551	Difficulty climbing stairs	Occasional (5-29%)
HP:0003557	Increased variability in muscle fiber diameter	Occasional (5-29%)
HP:0003700	Generalized amyotrophy	Occasional (5-29%)
HP:0006673	Reduced systolic function	Occasional (5-29%)
HP:0007110	Central hypoventilation	Occasional (5-29%)
HP:0007210	Lower limb amyotrophy	Occasional (5-29%)
HP:0007340	Lower limb muscle weakness	Occasional (5-29%)
HP:0008081	Pes valgus	Occasional (5-29%)
HP:0009046	Difficulty running	Occasional (5-29%)
HP:0010628	Facial palsy	Occasional (5-29%)
HP:0011703	Sinus tachycardia	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0030200	Fatiguable weakness of proximal limb muscles	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cap myopathy
Mondo ID	MONDO:0015753
MeSH	C579969
Orphanet	171881
SNOMED CT	703532002
UMLS	C3710589
MedGen	777197
GARD	0011915
Is cancer (heuristic)	no

Also known as: Cap disease · congenital myopathy with caps

Data availability: 1 ClinVar variant · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › alpha-actinopathy › cap myopathy

Related subtypes (3): congenital myopathy 2a, typical, autosomal dominant, progressive scapulohumeroperoneal distal myopathy, zebra body 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

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
31818	NM_032578.4(MYPN):c.2653C>T (p.Arg885Ter)	MYPN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 37 · Orphanet: 16 · 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
MYPN	Definitive	Autosomal recessive	MYPN-related myopathy	12
TPM3	Definitive	Autosomal dominant	TPM3-related myopathy	13
TPM2	Strong	Autosomal dominant	congenital myopathy 23	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYPN	Orphanet:154	Familial isolated dilated cardiomyopathy
MYPN	Orphanet:171439	Childhood-onset nemaline myopathy
MYPN	Orphanet:171881	Cap myopathy
MYPN	Orphanet:75249	Familial isolated restrictive cardiomyopathy
TPM2	Orphanet:1146	Distal arthrogryposis type 1
TPM2	Orphanet:1147	Sheldon-Hall syndrome
TPM2	Orphanet:171436	Typical nemaline myopathy
TPM2	Orphanet:171439	Childhood-onset nemaline myopathy
TPM2	Orphanet:171881	Cap myopathy
TPM2	Orphanet:2020	Congenital fiber-type disproportion myopathy
TPM3	Orphanet:171433	Intermediate nemaline myopathy
TPM3	Orphanet:171439	Childhood-onset nemaline myopathy
TPM3	Orphanet:171881	Cap myopathy
TPM3	Orphanet:178342	Inflammatory myofibroblastic tumor
TPM3	Orphanet:2020	Congenital fiber-type disproportion myopathy
TPM3	Orphanet:476406	Congenital generalized hypercontractile muscle stiffness syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYPN	HGNC:23246	ENSG00000138347	Q86TC9	Myopalladin	gencc,clinvar
TPM2	HGNC:12011	ENSG00000198467	P07951	Tropomyosin beta chain	gencc
TPM3	HGNC:12012	ENSG00000143549	P06753	Tropomyosin alpha-3 chain	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYPN	Myopalladin	Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines.
TPM2	Tropomyosin beta chain	Binds to actin filaments in muscle and non-muscle cells.
TPM3	Tropomyosin alpha-3 chain	Binds to actin filaments in muscle and non-muscle cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYPN	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
TPM2	Other/Unknown	no		Tropomyosin
TPM3	Other/Unknown	no		Tropomyosin

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	2
gastrocnemius	1
vastus lateralis	1
blood vessel layer	1
popliteal artery	1
saphenous vein	1
diaphragm	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYPN	116	broad	marker	hindlimb stylopod muscle, gastrocnemius, vastus lateralis
TPM2	283	ubiquitous	marker	saphenous vein, popliteal artery, blood vessel layer
TPM3	243	ubiquitous	marker	diaphragm, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPM3	4,099
MYPN	1,764
TPM2	357

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TPM3	P06753	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TPM2	P07951	91.51
MYPN	Q86TC9	52.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 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
Striated Muscle Contraction	2	308.6×	3e-05	TPM2, TPM3
Smooth Muscle Contraction	2	265.6×	3e-05	TPM2, TPM3
RHOV GTPase cycle	1	142.8×	0.009	TPM3
Signaling by ALK fusions and activated point mutants	1	75.1×	0.013	TPM3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
muscle contraction	2	138.7×	5e-04	TPM2, TPM3
actin filament organization	2	79.1×	7e-04	TPM2, TPM3
regulation of ATP-dependent activity	1	2808.7×	8e-04	TPM2
dendrite self-avoidance	1	351.1×	0.005	MYPN
sarcomere organization	1	127.7×	0.011	MYPN
homophilic cell-cell adhesion	1	46.8×	0.025	MYPN
axon guidance	1	30.2×	0.033	MYPN

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYPN	0	0
TPM2	0	0
TPM3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TPM3	18	Binding:18

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	MYPN
E	Difficult family or no structure, no drug	2	TPM2, TPM3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MYPN	0	—
TPM2	0	—
TPM3	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.