Congenital myasthenic syndrome 16

Summary

Congenital myasthenic syndrome 16 (MONDO:0013620) is a disease caused by SCN4A (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: SCN4A (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 608

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 16
Mondo ID	MONDO:0013620
OMIM	614198
DOID	DOID:0110682
UMLS	C3280112
MedGen	481742
GARD	0015771
Is cancer (heuristic)	no

Also known as: CMS16 · congenital myasthenic syndrome caused by mutation in SCN4A · congenital myasthenic syndrome type 16 · myasthenic syndrome, congenital, 16 · myasthenic syndrome, congenital, type 16 · SCN4A congenital myasthenic syndrome

Data availability: 608 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 › postsynaptic congenital myasthenic syndrome › congenital myasthenic syndrome 16

Related subtypes (13): congenital myasthenic syndrome 10, congenital myasthenic syndrome 1A, congenital myasthenic syndrome 8, congenital myasthenic syndrome 17, congenital myasthenic syndrome 2A, congenital myasthenic syndrome 2C, congenital myasthenic syndrome 3A, congenital myasthenic syndrome 3B, congenital myasthenic syndrome 3C, congenital myasthenic syndrome 9, congenital myasthenic syndrome 11, congenital myasthenic syndrome 19, congenital myasthenic syndrome 4

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

600 retrieved; paginated sample, class counts are floors:

331 uncertain significance, 129 conflicting classifications of pathogenicity, 41 likely benign, 36 benign, 31 benign/likely benign, 12 pathogenic, 11 likely pathogenic, 9 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3582645	NM_000334.4(SCN4A):c.4665del (p.Asn1556fs)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
427072	NM_000334.4(SCN4A):c.4776G>A (p.Met1592Ile)	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
5896	NM_000334.4(SCN4A):c.2111C>T (p.Thr704Met)	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
5899	NM_000334.4(SCN4A):c.4343G>A (p.Arg1448His)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
5900	NM_000334.4(SCN4A):c.3466G>A (p.Ala1156Thr)	GH-LCR	Pathogenic/Likely 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
5904	NM_000334.4(SCN4A):c.3938C>T (p.Thr1313Met)	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
5920	NM_000334.4(SCN4A):c.3917G>A (p.Gly1306Glu)	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
1032988	NM_000334.4(SCN4A):c.685del (p.Thr229fs)	SCN4A	Pathogenic	criteria provided, single submitter
143199	NM_000334.4(SCN4A):c.664C>T (p.Arg222Trp)	SCN4A	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
5910	NM_000334.4(SCN4A):c.1333G>A (p.Val445Met)	SCN4A	Pathogenic	criteria provided, multiple submitters, no conflicts
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
807677	NM_000334.4(SCN4A):c.3625T>C (p.Cys1209Arg)	SCN4A	Pathogenic	criteria provided, single submitter
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
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
1709301	NM_000334.4(SCN4A):c.435C>A (p.Cys145Ter)	SCN4A	Likely pathogenic	criteria provided, single submitter
2664731	NM_000334.4(SCN4A):c.3733G>A (p.Gly1245Ser)	SCN4A	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 10 · 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	Strong	Autosomal recessive	congenital myasthenic syndrome 16	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
RANBP2	Orphanet:178342	Inflammatory myofibroblastic tumor
RANBP2	Orphanet:263524	Acute necrotizing encephalopathy of childhood
RANBP2	Orphanet:88619	Familial acute necrotizing encephalopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	gencc,clinvar
RANBP2	HGNC:9848	ENSG00000153201	P49792	E3 SUMO-protein ligase RanBP2	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.
RANBP2	E3 SUMO-protein ligase RanBP2	E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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	55.8×	0.036
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN4A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a4su_mammal
RANBP2	Transcription factor	no		Ran_bind_dom, Znf_RanBP2, Cyclophilin-type_PPIase_dom

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
endothelial cell	1
mucosa of paranasal sinus	1
sperm	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
RANBP2	294	ubiquitous	marker	endothelial cell, sperm, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RANBP2	7,348
SCN4A	1,704

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RANBP2	P49792	33
SCN4A	P35499	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 2 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
IPs transport between nucleus and cytosol	1	190.3×	0.017	RANBP2
IP3 and IP4 transport between cytosol and nucleus	1	190.3×	0.017	RANBP2
IP6 and IP7 transport between cytosol and nucleus	1	190.3×	0.017	RANBP2
Interaction between L1 and Ankyrins	1	184.2×	0.017	SCN4A
Transport of Ribonucleoproteins into the Host Nucleus	1	178.4×	0.017	RANBP2
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	178.4×	0.017	RANBP2
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	178.4×	0.017	RANBP2
NEP/NS2 Interacts with the Cellular Export Machinery	1	173.0×	0.017	RANBP2
Phase 0 - rapid depolarisation	1	173.0×	0.017	SCN4A
Nuclear import of Rev protein	1	167.9×	0.017	RANBP2
Vpr-mediated nuclear import of PICs	1	167.9×	0.017	RANBP2
Transport of the SLBP independent Mature mRNA	1	163.1×	0.017	RANBP2
SUMOylation of SUMOylation proteins	1	163.1×	0.017	RANBP2
Transport of the SLBP Dependant Mature mRNA	1	158.6×	0.017	RANBP2
Rev-mediated nuclear export of HIV RNA	1	158.6×	0.017	RANBP2
Nuclear Pore Complex (NPC) Disassembly	1	154.3×	0.017	RANBP2
SUMOylation of ubiquitinylation proteins	1	146.4×	0.017	RANBP2
NS1 Mediated Effects on Host Pathways	1	142.8×	0.017	RANBP2
Transport of Mature mRNA Derived from an Intronless Transcript	1	135.9×	0.017	RANBP2
Viral Messenger RNA Synthesis	1	129.8×	0.017	RANBP2
SUMOylation of DNA replication proteins	1	124.1×	0.017	RANBP2
SUMOylation of RNA binding proteins	1	119.0×	0.017	RANBP2
snRNP Assembly	1	105.7×	0.018	RANBP2
tRNA processing in the nucleus	1	98.5×	0.019	RANBP2
SUMOylation of chromatin organization proteins	1	79.3×	0.021	RANBP2
Transport of Mature mRNA derived from an Intron-Containing Transcript	1	76.1×	0.021	RANBP2
ISG15 antiviral mechanism	1	75.1×	0.021	RANBP2
Signaling by ALK fusions and activated point mutants	1	75.1×	0.021	RANBP2
SUMOylation of DNA damage response and repair proteins	1	73.2×	0.021	RANBP2
Regulation of HSF1-mediated heat shock response	1	69.6×	0.021	RANBP2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of skeletal muscle contraction by action potential	1	8426.0×	0.002	SCN4A
nuclear export	1	766.0×	0.008	RANBP2
regulation of gluconeogenesis	1	561.7×	0.008	RANBP2
centrosome localization	1	443.5×	0.008	RANBP2
NLS-bearing protein import into nucleus	1	401.2×	0.008	RANBP2
cardiac muscle cell action potential involved in contraction	1	351.1×	0.008	SCN4A
intracellular glucose homeostasis	1	290.6×	0.008	RANBP2
response to amphetamine	1	247.8×	0.008	RANBP2
nucleocytoplasmic transport	1	195.9×	0.009	RANBP2
protein sumoylation	1	162.0×	0.010	RANBP2
sodium ion transport	1	135.9×	0.010	SCN4A
mRNA transport	1	131.7×	0.010	RANBP2
muscle contraction	1	104.0×	0.011	SCN4A
sodium ion transmembrane transport	1	101.5×	0.011	SCN4A
protein folding	1	51.7×	0.021	RANBP2
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	RANBP2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
RANBP2	0	0

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
RANBP2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	RANBP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RANBP2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.