congenital myopathy 4A, autosomal dominant

Summary

congenital myopathy 4A, autosomal dominant (MONDO:0800341) is a disease caused by variants in TPM3 and SELENON, with 3 cohort genes.

At a glance

• Causal genes: TPM3 (GenCC Definitive), SELENON (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myopathy 4A, autosomal dominant
Mondo ID	MONDO:0800341
OMIM	255310
GARD	0026509
Is cancer (heuristic)	no

Also known as: cap myopathy 1 · CAPM1 · CFTD · CFTDM · fiber-type disproportion myopathy, congenital · myopathy, congenital, with fiber-type disproportion · NEM1 · nemaline myopathy 1

Data availability: 28 ClinVar variants · 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 › TPM3-related myopathy › congenital myopathy 4A, autosomal dominant

Related subtypes (2): congenital myopathy 4B, autosomal recessive, cap 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

28 retrieved; paginated sample, class counts are floors:

10 pathogenic, 9 uncertain significance, 4 pathogenic/likely pathogenic, 4 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
4685499	NM_001100.4(ACTA1):c.925C>G (p.Pro309Ala)	ACTA1	Pathogenic	criteria provided, single submitter
1180703	NM_206926.2(SELENON):c.1344del (p.Asn449fs)	SELENON	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280366	NM_206926.2(SELENON):c.988C>T (p.Gln330Ter)	SELENON	Pathogenic	criteria provided, single submitter
4496	NM_206926.2(SELENON):c.841G>A (p.Gly281Ser)	SELENON	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12446	NM_152263.4(TPM3):c.26T>G (p.Met9Arg)	TPM3	Pathogenic	no assertion criteria provided
12449	NM_152263.4(TPM3):c.94C>T (p.Gln32Ter)	TPM3	Pathogenic	criteria provided, multiple submitters, no conflicts
12450	NM_152263.4(TPM3):c.503G>A (p.Arg168His)	TPM3	Pathogenic	criteria provided, multiple submitters, no conflicts
12452	NM_152263.4(TPM3):c.298C>A (p.Leu100Met)	TPM3	Pathogenic	no assertion criteria provided
12453	NM_152263.4(TPM3):c.502C>G (p.Arg168Gly)	TPM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12454	NM_152263.4(TPM3):c.502C>T (p.Arg168Cys)	TPM3	Pathogenic	criteria provided, multiple submitters, no conflicts
235143	NM_152263.4(TPM3):c.670GAA[1] (p.Glu225del)	TPM3	Pathogenic	no assertion criteria provided
2443942	NM_152263.4(TPM3):c.445C>A (p.Leu149Ile)	TPM3	Pathogenic	no assertion criteria provided
2882127	NM_152263.4(TPM3):c.138del (p.Met47fs)	TPM3	Pathogenic	criteria provided, single submitter
652762	NM_152263.4(TPM3):c.271C>T (p.Arg91Cys)	TPM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382549	NM_001100.4(ACTA1):c.355G>A (p.Glu119Lys)	ACTA1	Likely pathogenic	criteria provided, single submitter
212149	NM_206926.2(SELENON):c.725_727dup (p.Ala242_Cys243insSer)	SELENON	Likely pathogenic	criteria provided, multiple submitters, no conflicts
235144	NM_152263.4(TPM3):c.654AGA[1] (p.Glu219del)	TPM3	Likely pathogenic	criteria provided, single submitter
3899370	NM_152263.4(TPM3):c.452A>G (p.Glu151Gly)	TPM3	Likely pathogenic	criteria provided, single submitter
464134	NM_001100.4(ACTA1):c.811A>G (p.Met271Val)	ACTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2584979	NM_206926.2(SELENON):c.741C>G (p.Ile247Met)	SELENON	Uncertain significance	criteria provided, single submitter
1014108	NM_152263.4(TPM3):c.709G>A (p.Glu237Lys)	TPM3	Uncertain significance	criteria provided, single submitter
1064391	NM_152263.4(TPM3):c.832G>A (p.Ala278Thr)	TPM3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3068321	NM_152263.4(TPM3):c.723G>C (p.Glu241Asp)	TPM3	Uncertain significance	criteria provided, single submitter
3251966	NM_152263.4(TPM3):c.458_459insTAG (p.Lys153delinsAsnArg)	TPM3	Uncertain significance	criteria provided, single submitter
3892701	NM_001043353.2(TPM3):c.668G>A (p.Arg223His)	TPM3	Uncertain significance	criteria provided, single submitter
4086201	NM_152263.4(TPM3):c.424A>T (p.Met142Leu)	TPM3	Uncertain significance	criteria provided, single submitter
4292783	NM_152263.4(TPM3):c.284T>C (p.Leu95Pro)	TPM3	Uncertain significance	criteria provided, single submitter
4293438	NM_152263.4(TPM3):c.10G>A (p.Ala4Thr)	TPM3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 19 · 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
SELENON	Definitive	Autosomal recessive	SELENON-related myopathy	8
TPM3	Definitive	Autosomal dominant	TPM3-related myopathy	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
SELENON	Orphanet:2020	Congenital fiber-type disproportion myopathy
SELENON	Orphanet:324604	Classic multiminicore myopathy
SELENON	Orphanet:84132	Desmin-related myopathy with Mallory body-like inclusions
SELENON	Orphanet:97244	Rigid spine syndrome
ACTA1	Orphanet:171430	Severe congenital nemaline myopathy
ACTA1	Orphanet:171433	Intermediate nemaline myopathy
ACTA1	Orphanet:171436	Typical nemaline myopathy
ACTA1	Orphanet:171439	Childhood-onset nemaline myopathy
ACTA1	Orphanet:2020	Congenital fiber-type disproportion myopathy
ACTA1	Orphanet:447977	Progressive scapulohumeroperoneal distal myopathy
ACTA1	Orphanet:97240	Zebra body myopathy
ACTA1	Orphanet:97244	Rigid spine syndrome
ACTA1	Orphanet:98904	Congenital myopathy with excess of thin filaments

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
TPM3	HGNC:12012	ENSG00000143549	P06753	Tropomyosin alpha-3 chain	gencc,clinvar
SELENON	HGNC:15999	ENSG00000162430	Q9NZV5	Selenoprotein N	gencc,clinvar
ACTA1	HGNC:129	ENSG00000143632	P68133	Actin, alpha skeletal muscle	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPM3	Tropomyosin alpha-3 chain	Binds to actin filaments in muscle and non-muscle cells.
SELENON	Selenoprotein N	Plays an important role in cell protection against oxidative stress and in the regulation of redox-related calcium homeostasis.
ACTA1	Actin, alpha skeletal muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TPM3	Other/Unknown	no		Tropomyosin
SELENON	Other/Unknown	no		EF_hand_dom
ACTA1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS

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
diaphragm	2
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
ganglionic eminence	1
stromal cell of endometrium	1
ventricular zone	1
gluteal muscle	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPM3	243	ubiquitous	marker	diaphragm, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
SELENON	244	ubiquitous	marker	stromal cell of endometrium, ventricular zone, ganglionic eminence
ACTA1	203	broad	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPM3	4,099
SELENON	800
ACTA1	523

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTA1	P68133	5
TPM3	P06753	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SELENON	Q9NZV5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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×	1e-04	TPM3, ACTA1
Regulation of CDH1 Function	1	475.8×	0.011	ACTA1
Formation of the dystrophin-glycoprotein complex (DGC)	1	154.3×	0.015	ACTA1
RHOV GTPase cycle	1	142.8×	0.015	TPM3
Smooth Muscle Contraction	1	132.8×	0.015	TPM3
Activation of STAT3 by cadherin engagement	1	81.6×	0.017	ACTA1
Non-integrin membrane-ECM interactions	1	77.2×	0.017	ACTA1
Signaling by ALK fusions and activated point mutants	1	75.1×	0.017	TPM3
Muscle contraction	1	38.6×	0.029	ACTA1
Extracellular matrix organization	1	31.6×	0.031	ACTA1

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
skeletal muscle fiber development	2	362.4×	3e-04	SELENON, ACTA1
muscle contraction	2	138.7×	0.001	TPM3, ACTA1
positive regulation of skeletal muscle cell proliferation	1	2808.7×	0.003	SELENON
positive regulation of response to oxidative stress	1	2808.7×	0.003	SELENON
L-ascorbic acid transmembrane transport	1	1872.4×	0.003	SELENON
regulation of ryanodine-sensitive calcium-release channel activity	1	1872.4×	0.003	SELENON
diaphragm contraction	1	1404.3×	0.003	SELENON
response to muscle activity involved in regulation of muscle adaptation	1	1404.3×	0.003	SELENON
membrane biogenesis	1	1123.5×	0.003	SELENON
mesenchyme migration	1	1123.5×	0.003	ACTA1
skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration	1	936.2×	0.003	SELENON
membrane to membrane docking	1	936.2×	0.003	SELENON
skeletal muscle thin filament assembly	1	936.2×	0.003	ACTA1
skeletal muscle satellite cell differentiation	1	702.2×	0.003	SELENON
obsolete mitochondrion-endoplasmic reticulum membrane tethering	1	702.2×	0.003	SELENON
L-ascorbic acid metabolic process	1	510.7×	0.004	SELENON
cellular response to caffeine	1	510.7×	0.004	SELENON
multicellular organismal response to stress	1	432.1×	0.004	SELENON
energy reserve metabolic process	1	351.1×	0.005	SELENON
mitochondrial calcium ion transmembrane transport	1	330.4×	0.005	SELENON
calcium ion import	1	267.5×	0.006	SELENON
membrane organization	1	170.2×	0.009	SELENON
ATP metabolic process	1	156.0×	0.009	SELENON
calcium ion homeostasis	1	147.8×	0.010	SELENON
lung alveolus development	1	117.0×	0.011	SELENON
cell redox homeostasis	1	114.6×	0.011	SELENON
collagen fibril organization	1	74.9×	0.017	SELENON
response to endoplasmic reticulum stress	1	55.6×	0.022	SELENON
transforming growth factor beta receptor signaling pathway	1	53.0×	0.022	SELENON
cellular response to oxidative stress	1	51.5×	0.022	SELENON

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
TPM3	0	0
SELENON	0	0
ACTA1	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	0
E	Difficult family or no structure, no drug	3	TPM3, SELENON, ACTA1

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)
TPM3	18	—
SELENON	0	—
ACTA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.