Congenital myasthenic syndrome 11

Summary

Congenital myasthenic syndrome 11 (MONDO:0014588) is a disease caused by RAPSN (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: RAPSN (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 636

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 11
Mondo ID	MONDO:0014588
MeSH	C563831
OMIM	616326
DOID	DOID:0110675
UMLS	C4225367
MedGen	902189
GARD	0016089
Is cancer (heuristic)	no

Also known as: Cms Ie · CMS11 · congenital myasthenic syndrome caused by mutation in RAPSN · congenital myasthenic syndrome type 11 · myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency · myasthenic syndrome, congenital, Ie · RAPSN congenital myasthenic syndrome

Data availability: 636 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

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 11

Related subtypes (13): congenital myasthenic syndrome 10, congenital myasthenic syndrome 1A, congenital myasthenic syndrome 16, 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 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:

319 likely benign, 141 uncertain significance, 48 pathogenic, 30 conflicting classifications of pathogenicity, 28 pathogenic/likely pathogenic, 18 likely pathogenic, 10 benign, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067929	NM_005055.5(RAPSN):c.531+1G>T	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070359	NM_005055.5(RAPSN):c.418C>T (p.Gln140Ter)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072315	NM_005055.5(RAPSN):c.599G>A (p.Trp200Ter)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073877	NM_005055.5(RAPSN):c.291C>A (p.Cys97Ter)	RAPSN	Pathogenic	criteria provided, multiple submitters, no conflicts
1073878	NM_005055.5(RAPSN):c.46dup (p.Leu16fs)	RAPSN	Pathogenic	criteria provided, multiple submitters, no conflicts
1076821	NM_005055.5(RAPSN):c.838G>T (p.Gly280Ter)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323519	NM_005055.5(RAPSN):c.300_319del (p.His100fs)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324987	NM_005055.5(RAPSN):c.679G>T (p.Glu227Ter)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405025	NM_005055.5(RAPSN):c.537C>A (p.Tyr179Ter)	RAPSN	Pathogenic	criteria provided, single submitter
1407552	NM_005055.5(RAPSN):c.7C>T (p.Gln3Ter)	RAPSN	Pathogenic	criteria provided, single submitter
1416981	NM_005055.5(RAPSN):c.712C>T (p.Gln238Ter)	RAPSN	Pathogenic	criteria provided, multiple submitters, no conflicts
1417647	NM_005055.5(RAPSN):c.490C>G (p.Arg164Gly)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1426829	NM_005055.5(RAPSN):c.318C>A (p.Cys106Ter)	RAPSN	Pathogenic	criteria provided, single submitter
1454224	NM_005055.5(RAPSN):c.297del (p.His100fs)	RAPSN	Pathogenic	criteria provided, single submitter
1455976	NM_005055.5(RAPSN):c.210del (p.Ile70fs)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457721	NM_005055.5(RAPSN):c.546_547dup (p.Leu183fs)	RAPSN	Pathogenic	criteria provided, single submitter
1458342	NM_005055.5(RAPSN):c.1185del (p.Thr396fs)	RAPSN	Pathogenic	criteria provided, single submitter
1458494	NC_000011.9:g.(?47469557)(47478800_?)del	RAPSN	Pathogenic	criteria provided, single submitter
1481997	NM_005055.5(RAPSN):c.966+1_966+2delinsAG	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190252	NM_005055.5(RAPSN):c.1083_1084dup (p.Tyr362fs)	RAPSN	Pathogenic	criteria provided, multiple submitters, no conflicts
197248	NM_005055.5(RAPSN):c.737C>T (p.Ala246Val)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1997927	NM_005055.5(RAPSN):c.22C>T (p.Gln8Ter)	RAPSN	Pathogenic	criteria provided, single submitter
1997928	NM_005055.5(RAPSN):c.1A>G (p.Met1Val)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2034351	NM_005055.5(RAPSN):c.424_425insTGTCTCCTCTATATAAATGCGTAGGGGTTTTAGTTAAATGTCCTTTGAAGTATACTTGAGGAGGGTGACGGGCGGTGTGTACGCGCTTCAGGGCCCTGTTCAACTAAGCACTCTACCCTGTTCAACTAAG (p.Ala142delinsValSerProLeuTyrLysCysValGlyValLeuValLysCysProLeuLysTyrThrTer)	RAPSN	Pathogenic	criteria provided, single submitter
2077373	NM_005055.5(RAPSN):c.1168del (p.Cys390fs)	RAPSN	Pathogenic	criteria provided, single submitter
2099531	NM_005055.5(RAPSN):c.79C>T (p.Gln27Ter)	RAPSN	Pathogenic	criteria provided, single submitter
2137088	NM_005055.5(RAPSN):c.990_993del (p.His329_Cys330insTer)	RAPSN	Pathogenic	criteria provided, multiple submitters, no conflicts
2137089	NM_005055.5(RAPSN):c.973C>T (p.Gln325Ter)	RAPSN	Pathogenic	criteria provided, single submitter
2137090	NM_005055.5(RAPSN):c.358del (p.Gln120fs)	RAPSN	Pathogenic	criteria provided, single submitter
2152107	NM_005055.5(RAPSN):c.1166+1G>C	RAPSN	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
RAPSN	Strong	Autosomal recessive	congenital myasthenic syndrome 11	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAPSN	Orphanet:33108	Lethal multiple pterygium syndrome
RAPSN	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
RAPSN	Orphanet:994	Fetal akinesia deformation sequence
SPI1	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia

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
RAPSN	HGNC:9863	ENSG00000165917	Q13702	43 kDa receptor-associated protein of the synapse	gencc,clinvar
SPI1	HGNC:11241	ENSG00000066336	P17947	Transcription factor PU.1	clinvar
PSMC3	HGNC:9549	ENSG00000165916	P17980	26S proteasome regulatory subunit 6A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAPSN	43 kDa receptor-associated protein of the synapse	Postsynaptic protein required for clustering of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction.
SPI1	Transcription factor PU.1	Pioneer transcription factor, which controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing other transcription factors to enter otherwise inaccessible genomic sites.
PSMC3	26S proteasome regulatory subunit 6A	Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAPSN	Transcription factor	no		Postsynaptic, Znf_RING, TPR-like_helical_dom_sf
SPI1	Other/Unknown	no		Ets_dom, WH-like_DNA-bd_sf, WH_DNA-bd_sf
PSMC3	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_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
gastrocnemius	2
hindlimb stylopod muscle	1
male germ line stem cell (sensu Vertebrata) in testis	1
granulocyte	1
leukocyte	1
monocyte	1
apex of heart	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAPSN	159	tissue_specific	marker	hindlimb stylopod muscle, male germ line stem cell (sensu Vertebrata) in testis, gastrocnemius
SPI1	170	broad	marker	granulocyte, monocyte, leukocyte
PSMC3	289	ubiquitous	marker	apex of heart, gastrocnemius, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSMC3	4,843
SPI1	3,823
RAPSN	715

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSMC3	P17980	130
SPI1	P17947	35

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAPSN	Q13702	93.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 74. 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
RUNX1 regulates transcription of genes involved in differentiation of HSCs	2	95.2×	0.008	SPI1, PSMC3
Regulation of activated PAK-2p34 by proteasome mediated degradation	1	139.3×	0.018	PSMC3
Regulation of ornithine decarboxylase (ODC)	1	135.9×	0.018	PSMC3
Vpu mediated degradation of CD4	1	132.8×	0.018	PSMC3
Autodegradation of the E3 ubiquitin ligase COP1	1	132.8×	0.018	PSMC3
Ubiquitin-dependent degradation of Cyclin D	1	132.8×	0.018	PSMC3
Cross-presentation of soluble exogenous antigens (endosomes)	1	126.9×	0.018	PSMC3
Vif-mediated degradation of APOBEC3G	1	126.9×	0.018	PSMC3
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	124.1×	0.018	PSMC3
Degradation of AXIN	1	124.1×	0.018	PSMC3
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	1	124.1×	0.018	PSMC3
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	1	124.1×	0.018	PSMC3
Hh mutants are degraded by ERAD	1	121.5×	0.018	PSMC3
SCF-beta-TrCP mediated degradation of Emi1	1	119.0×	0.018	PSMC3
Degradation of DVL	1	119.0×	0.018	PSMC3
Negative regulation of NOTCH4 signaling	1	119.0×	0.018	PSMC3
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	1	119.0×	0.018	PSMC3
Regulation of RUNX3 expression and activity	1	116.5×	0.018	PSMC3
Somitogenesis	1	116.5×	0.018	PSMC3
NIK–>noncanonical NF-kB signaling	1	114.2×	0.018	PSMC3
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	114.2×	0.018	PSMC3
Degradation of GLI1 by the proteasome	1	112.0×	0.018	PSMC3
Degradation of GLI2 by the proteasome	1	112.0×	0.018	PSMC3
GLI3 is processed to GLI3R by the proteasome	1	112.0×	0.018	PSMC3
Defective CFTR causes cystic fibrosis	1	109.8×	0.018	PSMC3
Degradation of CRY and PER proteins	1	109.8×	0.018	PSMC3
Dectin-1 mediated noncanonical NF-kB signaling	1	107.7×	0.018	PSMC3
Hedgehog ligand biogenesis	1	105.7×	0.018	PSMC3
SCF(Skp2)-mediated degradation of p27/p21	1	103.8×	0.018	PSMC3
Asymmetric localization of PCP proteins	1	102.0×	0.018	PSMC3

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
host-mediated perturbation of viral transcription	1	5617.3×	0.003	PSMC3
regulation of postsynaptic membrane organization	1	5617.3×	0.003	RAPSN
establishment of protein localization to postsynaptic membrane	1	5617.3×	0.003	RAPSN
pro-T cell differentiation	1	2808.7×	0.003	SPI1
negative regulation of neutrophil degranulation	1	2808.7×	0.003	SPI1
regulation of myeloid progenitor cell differentiation	1	2808.7×	0.003	SPI1
positive regulation of myeloid dendritic cell chemotaxis	1	2808.7×	0.003	SPI1
positive regulation of motor neuron apoptotic process	1	2808.7×	0.003	RAPSN
myeloid leukocyte differentiation	1	1872.4×	0.003	SPI1
endothelial to hematopoietic transition	1	1872.4×	0.003	SPI1
positive regulation of neuromuscular synaptic transmission	1	1872.4×	0.003	RAPSN
positive regulation of antifungal innate immune response	1	1872.4×	0.003	SPI1
follicular B cell differentiation	1	1404.3×	0.003	SPI1
positive regulation of microglial cell mediated cytotoxicity	1	1404.3×	0.003	SPI1
negative regulation of MHC class II biosynthetic process	1	1123.5×	0.003	SPI1
anatomical structure regression	1	1123.5×	0.003	SPI1
pericyte cell differentiation	1	1123.5×	0.003	SPI1
regulation of erythrocyte differentiation	1	936.2×	0.003	SPI1
apoptotic process involved in blood vessel morphogenesis	1	936.2×	0.003	SPI1
immature B cell differentiation	1	802.5×	0.003	SPI1
oncogene-induced cell senescence	1	802.5×	0.003	SPI1
negative regulation of adipose tissue development	1	802.5×	0.003	SPI1
TRAIL-activated apoptotic signaling pathway	1	624.1×	0.004	SPI1
skeletal muscle acetylcholine-gated channel clustering	1	624.1×	0.004	RAPSN
germinal center B cell differentiation	1	561.7×	0.004	SPI1
negative regulation of protein localization to chromatin	1	510.7×	0.004	SPI1
defense response to tumor cell	1	432.1×	0.005	SPI1
granulocyte differentiation	1	401.2×	0.005	SPI1
positive regulation of B cell differentiation	1	374.5×	0.005	SPI1
interleukin-6-mediated signaling pathway	1	374.5×	0.005	SPI1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
PSMC3	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSMC3	2	4
RAPSN	0	0
SPI1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	PSMC3
CARFILZOMIB	4	PSMC3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSMC3	27	Binding:27
RAPSN	1	Binding:1

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

2 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)
BORTEZOMIB	4	PSMC3
CARFILZOMIB	4	PSMC3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSMC3
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	2	RAPSN, SPI1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RAPSN	1	—
SPI1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.