congenital myopathy 22A, classic

Summary

congenital myopathy 22A, classic (MONDO:0957247) is a disease caused by SCN4A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SCN4A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 269

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myopathy 22A, classic
Mondo ID	MONDO:0957247
OMIM	620351
DOID	DOID:0081354
UMLS	C5830453
MedGen	1841089
GARD	0026795
Is cancer (heuristic)	no

Data availability: 269 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital myopathy 22A, classic

Related subtypes (53): Ullrich congenital muscular dystrophy, congenital structural myopathy, Bethlem myopathy, MYH7-related skeletal myopathy, tubular aggregate myopathy, cylindrical spirals myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, intellectual disability-myopathy-short stature-endocrine defect syndrome, myopathy, myosin storage, autosomal recessive, Bailey-Bloch congenital myopathy, fingerprint body myopathy, myopathy, proximal, and ophthalmoplegia, Compton-North congenital myopathy, MEGF10-related myopathy, fetal akinesia-cerebral and retinal hemorrhage syndrome, Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome, severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome, myopathy with hexagonally cross-linked tubular arrays, benign Samaritan congenital myopathy, congenital generalized hypercontractile muscle stiffness syndrome, hyaline body myopathy, centronuclear myopathy, reducing body myopathy, myopathy, congenital, with tremor, myopathy, congenital, progressive, with scoliosis, myopathy, congenital, with structured cores and z-line abnormalities, myopathy, congenital, with respiratory insufficiency and bone fractures, myopathy, congenital proximal, with minicore lesions, myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, congenital myopathy with reduced type 2 muscle fibers, alpha-actinopathy, SELENON-related myopathy, TPM3-related myopathy, SCN4A-related myopathy, autosomal recessive, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, Batten-Turner congenital myopathy, TOR1AIP1-related myopathy, congenital myopathy 11, congenital myopathy 15, congenital myopathy 18, congenital myopathy 10b, mild variant, congenital myopathy 2b, severe infantile, autosomal recessive, congenital myopathy 2c, severe infantile, autosomal dominant, congenital myopathy 20, congenital myopathy 21 with early respiratory failure, congenital myopathy 22B, severe fetal, congenital myopathy 25, congenital myopathy 26, congenital myopathy 27, congenital myopathy 28 with rigid spine, congenital myopathy 29 with contractures

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

269 retrieved; paginated sample, class counts are floors:

199 uncertain significance, 44 conflicting classifications of pathogenicity, 11 likely pathogenic, 8 pathogenic, 6 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2501679	NM_000334.4(SCN4A):c.3626G>T (p.Cys1209Phe)	GH-LCR	Pathogenic	no assertion criteria provided
3582645	NM_000334.4(SCN4A):c.4665del (p.Asn1556fs)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
477417	NM_000334.4(SCN4A):c.3425G>A (p.Arg1142Gln)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
543801	NM_000334.4(SCN4A):c.5104G>A (p.Glu1702Lys)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5897	NM_000334.4(SCN4A):c.4774A>G (p.Met1592Val)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
5903	NM_000334.4(SCN4A):c.3917G>T (p.Gly1306Val)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
5919	NM_000334.4(SCN4A):c.2024G>A (p.Arg675Gln)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
633660	NM_000334.4(SCN4A):c.4379G>A (p.Arg1460Gln)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143201	NM_000334.4(SCN4A):c.3404G>A (p.Arg1135His)	SCN4A	Pathogenic	criteria provided, multiple submitters, no conflicts
2501683	NM_000334.4(SCN4A):c.1123T>C (p.Cys375Arg)	SCN4A	Pathogenic	no assertion criteria provided
5911	NM_000334.4(SCN4A):c.2006G>A (p.Arg669His)	SCN4A	Pathogenic	criteria provided, multiple submitters, no conflicts
5912	NM_000334.4(SCN4A):c.2015G>A (p.Arg672His)	SCN4A	Pathogenic	criteria provided, multiple submitters, no conflicts
591772	NM_000334.4(SCN4A):c.1173del (p.Phe392fs)	SCN4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
932430	NM_000334.4(SCN4A):c.4364T>C (p.Ile1455Thr)	SCN4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
243042	NM_000334.4(SCN4A):c.4360C>T (p.Arg1454Trp)	GH-LCR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2435732	NM_000334.4(SCN4A):c.3403C>T (p.Arg1135Cys)	GH-LCR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382003	NM_000334.4(SCN4A):c.3749T>G (p.Met1250Arg)	GH-LCR	Likely pathogenic	criteria provided, single submitter
3582627	NM_000334.4(SCN4A):c.5431_5434dup (p.Pro1812fs)	GH-LCR	Likely pathogenic	criteria provided, single submitter
3582635	NM_000334.4(SCN4A):c.5061_5062insAGGTGACT (p.Leu1688delinsArgTer)	GH-LCR	Likely pathogenic	criteria provided, single submitter
3582679	NM_000334.4(SCN4A):c.2377-1G>A	GH-LCR	Likely pathogenic	criteria provided, single submitter
3381979	NM_000334.4(SCN4A):c.1166del (p.Tyr389fs)	SCN4A	Likely pathogenic	criteria provided, single submitter
3582691	NM_000334.4(SCN4A):c.1452+1G>T	SCN4A	Likely pathogenic	criteria provided, single submitter
3582705	NM_000334.4(SCN4A):c.1043dup (p.Tyr349fs)	SCN4A	Likely pathogenic	criteria provided, single submitter
3582708	NM_000334.4(SCN4A):c.936G>A (p.Trp312Ter)	SCN4A	Likely pathogenic	criteria provided, single submitter
3582710	NM_000334.4(SCN4A):c.881G>A (p.Trp294Ter)	SCN4A	Likely pathogenic	criteria provided, single submitter
1034440	NM_000334.4(SCN4A):c.4827C>T (p.Ser1609=)	GH-LCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130233	NM_000334.4(SCN4A):c.3604G>A (p.Glu1202Lys)	GH-LCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
143200	NM_000334.4(SCN4A):c.3386G>A (p.Arg1129Gln)	GH-LCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1938919	NM_000334.4(SCN4A):c.4351C>T (p.Arg1451Cys)	GH-LCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
281372	NM_000334.4(SCN4A):c.3205G>A (p.Asp1069Asn)	GH-LCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 7 · 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
SCN4A	Definitive	Autosomal recessive	SCN4A-related myopathy, autosomal recessive	24

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN4A	Orphanet:681	Hypokalemic periodic paralysis
SCN4A	Orphanet:682	Hyperkalemic periodic paralysis
SCN4A	Orphanet:684	Paramyotonia congenita of Von Eulenburg
SCN4A	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
SCN4A	Orphanet:99734	Myotonia fluctuans
SCN4A	Orphanet:99735	Myotonia permanens
SCN4A	Orphanet:99736	Acetazolamide-responsive myotonia

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
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN4A	Sodium channel protein type 4 subunit alpha	Pore-forming subunit of Nav1.4, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN4A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a4su_mammal

Expression context

Cohort genes with no expression data: 0.

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
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN4A	153	tissue_specific	yes	hindlimb stylopod muscle, gastrocnemius, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCN4A	1,704

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN4A	P35499	3

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
Interaction between L1 and Ankyrins	1	368.4×	0.012	SCN4A
Phase 0 - rapid depolarisation	1	346.1×	0.012	SCN4A
L1CAM interactions	1	120.2×	0.018	SCN4A
Cardiac conduction	1	108.8×	0.018	SCN4A
Muscle contraction	1	77.2×	0.021	SCN4A
Axon guidance	1	45.1×	0.027	SCN4A
Nervous system development	1	42.9×	0.027	SCN4A
Developmental Biology	1	14.5×	0.069	SCN4A

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
regulation of skeletal muscle contraction by action potential	1	16852.0×	3e-04	SCN4A
cardiac muscle cell action potential involved in contraction	1	702.2×	0.004	SCN4A
sodium ion transport	1	271.8×	0.005	SCN4A
muscle contraction	1	208.1×	0.005	SCN4A
sodium ion transmembrane transport	1	203.0×	0.005	SCN4A

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
SCN4A	CARBAMAZEPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN4A	24	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CARBAMAZEPINE	4	SCN4A
PHENYTOIN	4	SCN4A
LAMOTRIGINE	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	SCN4A
SERTINDOLE	4	SCN4A
PIMOZIDE	4	SCN4A
NIFEDIPINE	4	SCN4A
DILTIAZEM	4	SCN4A
MIBEFRADIL	4	SCN4A
HALOPERIDOL	4	SCN4A
MEXILETINE	4	SCN4A
AMITRIPTYLINE	4	SCN4A
AMIODARONE	4	SCN4A
CHLORPROMAZINE	4	SCN4A
VIXOTRIGINE	3	SCN4A
ELECLAZINE	3	SCN4A
TETRODOTOXIN	3	SCN4A
TEDISAMIL	3	SCN4A
NITRENDIPINE	3	SCN4A
AJMALINE	3	SCN4A
PF-05089771	2	SCN4A
CIFENLINE	2	SCN4A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN4A	95	Binding:69, Functional:18, ADMET:7, Toxicity:1

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

24 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)
CARBAMAZEPINE	4	SCN4A
PHENYTOIN	4	SCN4A
LAMOTRIGINE	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	SCN4A
SERTINDOLE	4	SCN4A
PIMOZIDE	4	SCN4A
NIFEDIPINE	4	SCN4A
DILTIAZEM	4	SCN4A
MIBEFRADIL	4	SCN4A
HALOPERIDOL	4	SCN4A
MEXILETINE	4	SCN4A
AMITRIPTYLINE	4	SCN4A
AMIODARONE	4	SCN4A
CHLORPROMAZINE	4	SCN4A
VIXOTRIGINE	3	SCN4A
ELECLAZINE	3	SCN4A
TETRODOTOXIN	3	SCN4A
TEDISAMIL	3	SCN4A
NITRENDIPINE	3	SCN4A
AJMALINE	3	SCN4A
PF-05089771	2	SCN4A
CIFENLINE	2	SCN4A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN4A
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.