Congenital myasthenic syndrome 15

Summary

Congenital myasthenic syndrome 15 (MONDO:0014542) is a disease caused by ALG14 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ALG14 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 132

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 15
Mondo ID	MONDO:0014542
OMIM	616227
DOID	DOID:0110658
UMLS	C4015596
MedGen	864033
GARD	0018453
Is cancer (heuristic)	no

Also known as: ALG14 congenital myasthenic syndrome · CMS15 · congenital myasthenic syndrome caused by mutation in ALG14 · congenital myasthenic syndrome type 15 · myasthenic syndrome, congenital, 15 · myasthenic syndrome, congenital, 15, without tubular aggregates · myasthenic syndrome, congenital, type 15

Data availability: 132 ClinVar variants · 2 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 15

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

132 retrieved; paginated sample, class counts are floors:

65 uncertain significance, 54 likely benign, 7 conflicting classifications of pathogenicity, 3 benign, 2 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
183013	NM_144988.4(ALG14):c.194C>T (p.Pro65Leu)	ALG14-AS1	Pathogenic	no assertion criteria provided
1356542	NM_144988.4(ALG14):c.16G>A (p.Val6Ile)	ALG14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
183014	NM_144988.4(ALG14):c.310C>T (p.Arg104Ter)	ALG14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287329	NM_144988.4(ALG14):c.113G>T (p.Ser38Ile)	ALG14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
933844	NM_144988.4(ALG14):c.83C>A (p.Ser28Tyr)	ALG14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
978234	NM_144988.4(ALG14):c.420+6_420+9del	ALG14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
389968	NM_144988.4(ALG14):c.220G>A (p.Asp74Asn)	ALG14-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
662491	NM_144988.4(ALG14):c.136+1G>C	LOC129930989	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1017450	NM_144988.4(ALG14):c.533T>G (p.Val178Gly)	ALG14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1037915	NM_144988.4(ALG14):c.641G>A (p.Arg214Gln)	ALG14	Uncertain significance	criteria provided, single submitter
1045564	NM_144988.4(ALG14):c.599C>T (p.Pro200Leu)	ALG14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1045748	NM_144988.4(ALG14):c.289-2A>G	ALG14	Uncertain significance	criteria provided, single submitter
1046647	NM_144988.4(ALG14):c.342_344del (p.Trp115del)	ALG14	Uncertain significance	criteria provided, single submitter
1047475	NM_144988.4(ALG14):c.191C>T (p.Ser64Leu)	ALG14	Uncertain significance	criteria provided, single submitter
1058515	NM_144988.4(ALG14):c.280A>G (p.Ser94Gly)	ALG14	Uncertain significance	criteria provided, single submitter
1304004	NM_144988.4(ALG14):c.323G>A (p.Ser108Asn)	ALG14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1361709	NM_144988.4(ALG14):c.248C>A (p.Ser83Tyr)	ALG14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1364291	NM_144988.4(ALG14):c.181A>G (p.Asn61Asp)	ALG14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1370026	NM_144988.4(ALG14):c.503T>G (p.Ile168Ser)	ALG14	Uncertain significance	criteria provided, single submitter
1392947	NM_144988.4(ALG14):c.328G>A (p.Glu110Lys)	ALG14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1408192	NM_144988.4(ALG14):c.109C>T (p.Leu37Phe)	ALG14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1411371	NM_144988.4(ALG14):c.532G>A (p.Val178Ile)	ALG14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1412749	NC_000001.10:g.(?95538299)(95538454_?)del	ALG14	Uncertain significance	criteria provided, single submitter
1413903	NM_144988.4(ALG14):c.66A>G (p.Ile22Met)	ALG14	Uncertain significance	criteria provided, single submitter
1421403	NM_144988.4(ALG14):c.476T>C (p.Leu159Pro)	ALG14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1423184	NM_144988.4(ALG14):c.551C>G (p.Ser184Cys)	ALG14	Uncertain significance	criteria provided, single submitter
1444164	NC_000001.10:g.(?95448632)(95538454_?)dup	ALG14	Uncertain significance	criteria provided, single submitter
1444819	NM_144988.4(ALG14):c.560T>C (p.Ile187Thr)	ALG14	Uncertain significance	criteria provided, single submitter
1474141	NM_144988.4(ALG14):c.464C>T (p.Ser155Phe)	ALG14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1505051	NM_144988.4(ALG14):c.539C>T (p.Thr180Met)	ALG14	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
ALG14	Strong	Autosomal recessive	congenital myasthenic syndrome 15	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALG14	Orphanet:353327	Congenital myasthenic syndrome with glycosylation defect

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALG14	HGNC:28287	ENSG00000172339	Q96F25	UDP-N-acetylglucosamine transferase subunit ALG14	gencc,clinvar
CNN3-DT	HGNC:54176	ENSG00000235501		CNN3 divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALG14	UDP-N-acetylglucosamine transferase subunit ALG14	Part of the UDP-N-acetylglucosamine transferase complex that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALG14	Other/Unknown	no		Oligosacch_biosynth_Alg14
CNN3-DT	Other/Unknown	no

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
colonic mucosa	1
corpus epididymis	1
jejunal mucosa	1
left adrenal gland cortex	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALG14	235	ubiquitous	marker	corpus epididymis, jejunal mucosa, colonic mucosa
CNN3-DT	189	ubiquitous	marker	right adrenal gland, left adrenal gland cortex, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALG14	708
CNN3-DT	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALG14	Q96F25	91.06

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 ALG14 causes ALG14-CMS	1	5710.0×	0.002	ALG14
Diseases associated with N-glycosylation of proteins	1	634.4×	0.007	ALG14
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	207.6×	0.014	ALG14
Diseases of glycosylation	1	131.3×	0.017	ALG14
Diseases of metabolism	1	80.4×	0.022	ALG14
Asparagine N-linked glycosylation	1	60.1×	0.025	ALG14
Post-translational protein modification	1	19.2×	0.067	ALG14
Disease	1	13.1×	0.081	ALG14
Metabolism of proteins	1	12.4×	0.081	ALG14

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
dolichol-linked oligosaccharide biosynthetic process	1	842.6×	0.002	ALG14
protein N-linked glycosylation	1	263.3×	0.004	ALG14

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALG14	0	0
CNN3-DT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	ALG14, CNN3-DT

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)
ALG14	0	—
CNN3-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.