Congenital myasthenic syndrome 14

Summary

Congenital myasthenic syndrome 14 (MONDO:0014543) is a disease caused by ALG2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ALG2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 298

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 14
Mondo ID	MONDO:0014543
OMIM	616228
DOID	DOID:0110669
UMLS	C4015597
MedGen	864034
GARD	0018454
Is cancer (heuristic)	no

Also known as: ALG2 congenital myasthenic syndromes with glycosylation defect · CMS14 · CMSTA3 · congenital myasthenic syndrome 14 · congenital myasthenic syndrome type 14 · congenital myasthenic syndromes with glycosylation defect caused by mutation in ALG2 · myasthenic syndrome, congenital, 14 · myasthenic syndrome, congenital, 14, with tubular aggregates · myasthenic syndrome, congenital, type 14

Data availability: 298 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 › congenital myasthenic syndrome with tubular aggregates › congenital myasthenic syndrome 14

Related subtypes (2): congenital myasthenic syndrome 12, congenital myasthenic syndrome 13

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

298 retrieved; paginated sample, class counts are floors:

157 uncertain significance, 116 likely benign, 7 conflicting classifications of pathogenicity, 6 benign, 6 benign/likely benign, 3 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
183018	NM_033087.4(ALG2):c.214_224delinsAGTCCCCG (p.Gly72_Leu75delinsSerProArg)	ALG2	Pathogenic	criteria provided, single submitter
183019	NM_033087.4(ALG2):c.203T>G (p.Val68Gly)	ALG2	Pathogenic	no assertion criteria provided
2699	NM_033087.4(ALG2):c.1040del (p.Gly347fs)	ALG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
992273	NM_033087.4(ALG2):c.215_225del (p.Gly72fs)	ALG2	Pathogenic	no assertion criteria provided
2498382	NM_033087.4(ALG2):c.1193T>C (p.Phe398Ser)	ALG2	Likely pathogenic	no assertion criteria provided
3779328	NM_033087.4(ALG2):c.814G>T (p.Glu272Ter)	ALG2	Likely pathogenic	criteria provided, single submitter
1041171	NM_033087.4(ALG2):c.945C>T (p.Cys315=)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2146428	NM_033087.4(ALG2):c.1133G>A (p.Arg378His)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
390397	NM_033087.4(ALG2):c.475A>G (p.Ile159Val)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464893	NM_033087.4(ALG2):c.1055_1056delinsTGA (p.Ser352fs)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464895	NM_033087.4(ALG2):c.348+6G>A	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
856875	NM_033087.4(ALG2):c.20G>A (p.Arg7Gln)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
952342	NM_033087.4(ALG2):c.1226G>A (p.Arg409Gln)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000582	NM_033087.4(ALG2):c.202G>A (p.Val68Met)	ALG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1004082	NM_033087.4(ALG2):c.703G>A (p.Glu235Lys)	ALG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1016801	NM_033087.4(ALG2):c.30del (p.Ser11fs)	ALG2	Uncertain significance	criteria provided, single submitter
1017971	NM_033087.4(ALG2):c.389G>A (p.Arg130Gln)	ALG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1021130	NM_033087.4(ALG2):c.1054_1055insTGA (p.Ser352delinsLeuThr)	ALG2	Uncertain significance	criteria provided, single submitter
1027185	NM_033087.4(ALG2):c.1115C>T (p.Ala372Val)	ALG2	Uncertain significance	criteria provided, single submitter
1035954	NM_033087.4(ALG2):c.89_114del (p.Glu30fs)	ALG2	Uncertain significance	criteria provided, single submitter
1039238	NM_033087.4(ALG2):c.1218G>C (p.Gln406His)	ALG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1041393	NM_033087.4(ALG2):c.367G>A (p.Val123Met)	ALG2	Uncertain significance	criteria provided, single submitter
1047589	NM_033087.4(ALG2):c.434C>T (p.Thr145Ile)	ALG2	Uncertain significance	criteria provided, single submitter
1053713	NM_033087.4(ALG2):c.1156_1162del (p.Met386fs)	ALG2	Uncertain significance	criteria provided, single submitter
1059228	NM_033087.4(ALG2):c.1239A>C (p.Lys413Asn)	ALG2	Uncertain significance	criteria provided, single submitter
1062878	NM_033087.4(ALG2):c.214G>A (p.Gly72Arg)	ALG2	Uncertain significance	criteria provided, single submitter
1063273	NM_033087.4(ALG2):c.32C>T (p.Ser11Leu)	ALG2	Uncertain significance	criteria provided, single submitter
1063530	NM_033087.4(ALG2):c.361A>G (p.Ile121Val)	ALG2	Uncertain significance	criteria provided, single submitter
1319358	NM_033087.4(ALG2):c.19C>T (p.Arg7Trp)	ALG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1349332	NM_033087.4(ALG2):c.17G>T (p.Gly6Val)	ALG2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
ALG2	Strong	Autosomal recessive	congenital myasthenic syndrome 14	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALG2	Orphanet:353327	Congenital myasthenic syndrome with glycosylation defect
ALG2	Orphanet:79326	ALG2-CDG

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
ALG2	HGNC:23159	ENSG00000119523	Q9H553	Alpha-1,3/1,6-mannosyltransferase ALG2	gencc,clinvar
ANP32B	HGNC:16677	ENSG00000136938	Q92688	Acidic leucine-rich nuclear phosphoprotein 32 family member B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALG2	Alpha-1,3/1,6-mannosyltransferase ALG2	Mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
ANP32B	Acidic leucine-rich nuclear phosphoprotein 32 family member B	Multifunctional protein that is involved in the regulation of many processes including cell proliferation, apoptosis, cell cycle progression or transcription.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALG2	Enzyme (other)	yes	2.4.1.132	Glyco_trans_1, ALG2, Glyco_trans_4-like_N
ANP32B	Other/Unknown	no		Leu-rich_rpt, U2A’_phosphoprotein32A_C, LRR_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caput epididymis	1
corpus epididymis	1
epithelial cell of pancreas	1
cranial nerve II	1
tendon of biceps brachii	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALG2	256	ubiquitous	marker	epithelial cell of pancreas, corpus epididymis, caput epididymis
ANP32B	295	ubiquitous	marker	tendon of biceps brachii, trabecular bone tissue, cranial nerve II

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALG2	1,967
ANP32B	339

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANP32B	Q92688	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALG2	Q9H553	91.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 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
Defective ALG2 causes CDG-1i	1	11420.0×	8e-04	ALG2
Diseases associated with N-glycosylation of proteins	1	634.4×	0.007	ALG2
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	207.6×	0.014	ALG2
Diseases of glycosylation	1	131.3×	0.017	ALG2
Diseases of metabolism	1	80.4×	0.022	ALG2
Asparagine N-linked glycosylation	1	60.1×	0.025	ALG2
Post-translational protein modification	1	19.2×	0.067	ALG2
Disease	1	13.1×	0.081	ALG2
Metabolism of proteins	1	12.4×	0.081	ALG2

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
vasculature development	1	561.7×	0.007	ANP32B
dolichol-linked oligosaccharide biosynthetic process	1	421.3×	0.007	ALG2
ventricular system development	1	421.3×	0.007	ANP32B
positive regulation of protein export from nucleus	1	401.2×	0.007	ANP32B
inner ear development	1	187.2×	0.011	ANP32B
glycoprotein biosynthetic process	1	168.5×	0.011	ALG2
negative regulation of cell differentiation	1	142.8×	0.011	ANP32B
protein N-linked glycosylation	1	131.7×	0.011	ALG2
roof of mouth development	1	123.9×	0.011	ANP32B
nucleosome assembly	1	70.2×	0.017	ANP32B
regulation of apoptotic process	1	41.7×	0.026	ANP32B
negative regulation of apoptotic process	1	17.4×	0.057	ANP32B

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ANP32B	1	2
ALG2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ANP32B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ANP32B	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALG2	2.4.1.132, 2.4.1.257	GDP-Man:Man1GlcNAc2-PP-dolichol alpha-1,3-mannosyltransferase, GDP-Man:Man2GlcNAc2-PP-dolichol alpha-1,6-mannosyltransferase

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

1 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)
MOLIBRESIB	2	ANP32B

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	1	ANP32B
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ALG2
E	Difficult family or no structure, no drug	0

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)
ALG2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.