congenital myasthenic syndrome 4C

Summary

congenital myasthenic syndrome 4C (MONDO:0012157) is a disease caused by CHRNE (GenCC Strong), with 8 cohort genes.

At a glance

• Causal gene: CHRNE (GenCC Strong)
• Cohort genes: 8
• ClinVar variants: 178

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 4C
Mondo ID	MONDO:0012157
OMIM	608931
DOID	DOID:0110679
UMLS	C1837091
MedGen	373251
GARD	0010108
Is cancer (heuristic)	no

Also known as: Cms Id · CMS4C · congenital myasthenic syndrome associated with acetylcholine receptor deficiency · congenital myasthenic syndrome type 4C · myasthenia, familial infantile, 1 · myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency · myasthenic syndrome, congenital, associated with acetylcholine receptor deficiency

Data availability: 178 ClinVar variants · 1 GenCC gene-disease record · 3 cell lines.

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 4 › congenital myasthenic syndrome 4C

Related subtypes (2): congenital myasthenic syndrome 4A, congenital myasthenic syndrome 4B

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

178 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 33 conflicting classifications of pathogenicity, 30 pathogenic/likely pathogenic, 24 likely pathogenic, 23 pathogenic, 15 benign, 6 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1299524	NM_000048.4(ASL):c.1327del (p.Thr443fs)	ASL	Pathogenic	criteria provided, single submitter
18345	NM_000080.4(CHRNE):c.500G>T (p.Arg167Leu)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18347	NM_000080.4(CHRNE):c.250C>T (p.Arg84Ter)	C17orf107	Pathogenic	criteria provided, multiple submitters, no conflicts
18357	NM_000080.4(CHRNE):c.614_620del (p.Trp205fs)	C17orf107	Pathogenic	criteria provided, multiple submitters, no conflicts
243031	NM_000080.4(CHRNE):c.1327del	C17orf107	Pathogenic	criteria provided, multiple submitters, no conflicts
372325	NM_000080.4(CHRNE):c.905C>G (p.Pro302Arg)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449451	NM_000080.4(CHRNE):c.934_936del (p.Met312del)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
465864	NM_000080.4(CHRNE):c.764C>T (p.Ser255Leu)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
534249	NM_000080.4(CHRNE):c.293T>C (p.Leu98Pro)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
567393	NM_000080.4(CHRNE):c.794del (p.Pro265fs)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694659	NM_000080.4(CHRNE):c.442T>A (p.Cys148Ser)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
803298	NM_000080.4(CHRNE):c.854T>C (p.Val285Ala)	C17orf107	Pathogenic	criteria provided, single submitter
863073	NM_000080.4(CHRNE):c.803-2A>G	C17orf107	Pathogenic	criteria provided, multiple submitters, no conflicts
813415	NM_020549.5(CHAT):c.982del (p.Asp328fs)	CHAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1417628	NM_000080.4(CHRNE):c.847C>T (p.Gln283Ter)	CHRNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454210	NM_000080.4(CHRNE):c.105T>A (p.Tyr35Ter)	CHRNE	Pathogenic	criteria provided, multiple submitters, no conflicts
1458892	NM_000080.4(CHRNE):c.1219+2T>G	CHRNE	Pathogenic	criteria provided, multiple submitters, no conflicts
1694812	NM_000080.4(CHRNE):c.1255G>T (p.Glu419Ter)	CHRNE	Pathogenic	criteria provided, multiple submitters, no conflicts
18346	NM_000080.4(CHRNE):c.422C>T (p.Pro141Leu)	CHRNE	Pathogenic	criteria provided, multiple submitters, no conflicts
18348	NM_000080.4(CHRNE):c.971del (p.Ile324fs)	CHRNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18349	NM_000080.4(CHRNE):c.344+1G>A	CHRNE	Pathogenic	no assertion criteria provided
18350	NM_000080.4(CHRNE):c.1030del (p.His344fs)	CHRNE	Pathogenic	no assertion criteria provided
18355	NM_000080.4(CHRNE):c.1161_1162insT (p.Lys388Ter)	CHRNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18358	NM_000080.4(CHRNE):c.991C>T (p.Arg331Trp)	CHRNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18361	NM_000080.4(CHRNE):c.1291G>C (p.Ala431Pro)	CHRNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189225	NM_000080.4(CHRNE):c.1033-2A>T	CHRNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2170253	NM_000080.4(CHRNE):c.1192C>T (p.Gln398Ter)	CHRNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
243030	NM_000080.4(CHRNE):c.130dup (p.Glu44fs)	CHRNE	Pathogenic	criteria provided, multiple submitters, no conflicts
243032	NM_000080.4(CHRNE):c.1353dup (p.Asn452fs)	CHRNE	Pathogenic	criteria provided, multiple submitters, no conflicts
2498162	NM_000080.4(CHRNE):c.1032+1G>C	CHRNE	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
CHRNE	Definitive	Autosomal recessive	congenital myasthenic syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHRNE	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
CHAT	Orphanet:98914	Presynaptic congenital myasthenic syndromes
CHRNB1	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
GFPT1	Orphanet:353327	Congenital myasthenic syndrome with glycosylation defect
ASL	Orphanet:23	Argininosuccinic aciduria
MUSK	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
MUSK	Orphanet:994	Fetal akinesia deformation sequence
RAPSN	Orphanet:33108	Lethal multiple pterygium syndrome
RAPSN	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
RAPSN	Orphanet:994	Fetal akinesia deformation sequence

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CHRNE	HGNC:1966	ENSG00000108556	Q04844	Acetylcholine receptor subunit epsilon	gencc,clinvar
CHAT	HGNC:1912	ENSG00000070748	P28329	Choline O-acetyltransferase	clinvar
CHRNB1	HGNC:1961	ENSG00000170175	P11230	Acetylcholine receptor subunit beta	clinvar
C17orf107	HGNC:37238	ENSG00000205710	Q6ZR85	Uncharacterized protein C17orf107	clinvar
GFPT1	HGNC:4241	ENSG00000198380	Q06210	Glutamine–fructose-6-phosphate aminotransferase [isomerizing] 1	clinvar
ASL	HGNC:746	ENSG00000126522	P04424	Argininosuccinate lyase	clinvar
MUSK	HGNC:7525	ENSG00000030304	O15146	Muscle, skeletal receptor tyrosine-protein kinase	clinvar
RAPSN	HGNC:9863	ENSG00000165917	Q13702	43 kDa receptor-associated protein of the synapse	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHRNE	Acetylcholine receptor subunit epsilon	After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
CHAT	Choline O-acetyltransferase	Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses.
CHRNB1	Acetylcholine receptor subunit beta	After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
GFPT1	Glutamine–fructose-6-phosphate aminotransferase [isomerizing] 1	Rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP) that catalyzes the formation of glucosamine-6-phosphate from fructose-6-phosphate and glutamine, thereby controlling the flux of glucose into this pathway.
ASL	Argininosuccinate lyase	Catalyzes the reversible cleavage of L-argininosuccinate to fumarate and L-arginine, an intermediate step reaction in the urea cycle mostly providing for hepatic nitrogen detoxification into excretable urea as well as de novo L-arginine sy…
MUSK	Muscle, skeletal receptor tyrosine-protein kinase	Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle.
RAPSN	43 kDa receptor-associated protein of the synapse	Postsynaptic protein required for clustering of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 3 · 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)	3	4.5×	0.094
Kinase	1	3.5×	0.509
Transcription factor	1	1.0×	0.859
Other/Unknown	3	0.7×	0.919

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHRNE	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
CHAT	Enzyme (other)	yes	2.3.1.6	Carn_acyl_trans, CAT-like_dom_sf, Cho/carn_acyl_trans_1_2
CHRNB1	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
C17orf107	Other/Unknown	no		C17orf107
GFPT1	Enzyme (other)	yes	2.6.1.16	SIS_dom, GFAT, GATase_2_dom
ASL	Enzyme (other)	yes	4.3.2.1	Fumarate_lyase_fam, L-Aspartase-like, Argininosuccinate_lyase
MUSK	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
RAPSN	Transcription factor	no		Postsynaptic, Znf_RING, TPR-like_helical_dom_sf

Expression context

Cohort genes with no expression data: 0.

6 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	3
adenohypophysis	2
right atrium auricular region	2
gastrocnemius	2
hindlimb stylopod muscle	2
cardiac atrium	1
primordial germ cell in gonad	1
putamen	1
muscle of leg	1
pituitary gland	1
colonic mucosa	1
mucosa of sigmoid colon	1
secondary oocyte	1
liver	1
mucosa of transverse colon	1
right lobe of liver	1
mucosa of stomach	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHRNE	162	broad	yes	right atrium auricular region, cardiac atrium, adenohypophysis
CHAT	68	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, putamen
CHRNB1	137	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, muscle of leg
C17orf107	131	broad	yes	adenohypophysis, pituitary gland, right atrium auricular region
GFPT1	287	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, secondary oocyte
ASL	145	ubiquitous	marker	right lobe of liver, liver, mucosa of transverse colon
MUSK	151	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, mucosa of stomach, sural nerve
RAPSN	159	tissue_specific	marker	hindlimb stylopod muscle, male germ line stem cell (sensu Vertebrata) in testis, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 10.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GFPT1	2,798
MUSK	1,809
CHAT	1,743
ASL	1,486
CHRNE	896
RAPSN	715
CHRNB1	711
C17orf107	110

Intra-cohort edges

A	B	Sources
C17orf107	CHRNE	string_interaction
CHRNB1	CHRNE	string_interaction
CHRNB1	GFPT1	string_interaction
CHRNB1	MUSK	string_interaction
CHRNB1	RAPSN	string_interaction
CHRNE	GFPT1	string_interaction
CHRNE	MUSK	string_interaction
CHRNE	RAPSN	string_interaction
GFPT1	RAPSN	string_interaction
MUSK	RAPSN	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GFPT1	Q06210	16
CHRNE	Q04844	13
CHRNB1	P11230	13
CHAT	P28329	8
MUSK	O15146	4
ASL	P04424	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAPSN	Q13702	93.29
C17orf107	Q6ZR85	58.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 8 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GFPT1 causes CMSTA1	1	2284.0×	0.004	GFPT1
ASL variants cause argininosuccinate aciduria	1	2284.0×	0.004	ASL
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	1	326.3×	0.014	CHRNE
Synthesis of UDP-N-acetyl-glucosamine	1	285.5×	0.014	GFPT1
Presynaptic nicotinic acetylcholine receptors	1	190.3×	0.014	CHRNE
Urea cycle	1	175.7×	0.014	ASL
Acetylcholine binding and downstream events	1	163.1×	0.014	CHRNE
Postsynaptic nicotinic acetylcholine receptors	1	163.1×	0.014	CHRNE
Acetylcholine Neurotransmitter Release Cycle	1	134.3×	0.015	CHAT
Synthesis of PC	1	81.6×	0.022	CHAT
XBP1(S) activates chaperone genes	1	43.1×	0.038	GFPT1
ECM proteoglycans	1	30.1×	0.049	MUSK
Neurotransmitter receptors and postsynaptic signal transmission	1	20.0×	0.068	CHRNE
Transmission across Chemical Synapses	1	15.2×	0.082	CHRNE
Metabolism of amino acids and derivatives	1	13.5×	0.086	ASL
Extracellular matrix organization	1	12.6×	0.086	MUSK
Neuronal System	1	8.8×	0.114	CHRNE
Metabolism	1	2.3×	0.362	ASL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
synaptic transmission, cholinergic	3	343.9×	3e-06	CHRNE, CHRNB1, RAPSN
skeletal muscle acetylcholine-gated channel clustering	2	535.0×	1e-04	MUSK, RAPSN
acetylcholine receptor signaling pathway	2	178.3×	6e-04	CHRNE, CHRNB1
neuromuscular synaptic transmission	2	172.0×	6e-04	CHAT, CHRNB1
skeletal muscle contraction	2	145.9×	6e-04	CHRNE, CHRNB1
membrane depolarization	2	145.9×	6e-04	CHRNE, CHRNB1
ammonia assimilation cycle	1	2407.4×	0.002	ASL
regulation of postsynaptic membrane organization	1	2407.4×	0.002	RAPSN
establishment of protein localization to postsynaptic membrane	1	2407.4×	0.002	RAPSN
positive regulation of protein geranylgeranylation	1	2407.4×	0.002	MUSK
muscle contraction	2	59.4×	0.002	CHRNE, CHRNB1
monoatomic ion transmembrane transport	2	59.4×	0.002	CHRNE, CHRNB1
obsolete L-arginine biosynthetic process via ornithine	1	1203.7×	0.003	ASL
positive regulation of motor neuron apoptotic process	1	1203.7×	0.003	RAPSN
L-arginine biosynthetic process	1	802.5×	0.003	ASL
acetylcholine biosynthetic process	1	802.5×	0.003	CHAT
positive regulation of neuromuscular synaptic transmission	1	802.5×	0.003	RAPSN
postsynaptic membrane organization	1	601.9×	0.004	CHRNB1
UDP-N-acetylglucosamine metabolic process	1	401.2×	0.006	GFPT1
arginine metabolic process	1	343.9×	0.007	ASL
chemical synaptic transmission	2	22.1×	0.008	CHRNE, RAPSN
behavioral response to nicotine	1	267.5×	0.008	CHRNB1
regulation of synaptic assembly at neuromuscular junction	1	240.7×	0.008	MUSK
UDP-N-acetylglucosamine biosynthetic process	1	218.9×	0.009	GFPT1
urea cycle	1	185.2×	0.010	ASL
nervous system process	1	172.0×	0.010	CHRNB1
fructose 6-phosphate metabolic process	1	160.5×	0.010	GFPT1
motor neuron apoptotic process	1	160.5×	0.010	RAPSN
energy reserve metabolic process	1	150.5×	0.011	GFPT1
muscle cell development	1	133.8×	0.012	CHRNB1

Therapeutics

Drug target analysis

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

Druggability breadth: 6 of 8 evidence-associated genes (75%) 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
CHRNE	MECAMYLAMINE
CHRNB1	VARENICLINE
MUSK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MUSK	20	4
CHRNB1	10	4
CHRNE	4	4
CHAT	1	3
C17orf107	0	0
GFPT1	0	0
ASL	0	0
RAPSN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MECAMYLAMINE	4	CHRNB1, CHRNE
NICOTINE	4	CHRNB1, CHRNE
DONEPEZIL	4	CHRNE
TACRINE	4	CHRNE
VARENICLINE	4	CHRNB1
TROPISETRON	4	CHRNB1
BUPROPION	4	CHRNB1
FEDRATINIB	4	MUSK
SORAFENIB	4	MUSK
NINTEDANIB	4	MUSK
SUNITINIB	4	MUSK
QUIZARTINIB	4	MUSK
CRIZOTINIB	4	MUSK
COENZYME_A	3	CHAT
DEXMECAMYLAMINE	3	CHRNB1
CYTISINICLINE	3	CHRNB1
LINIFANIB	3	MUSK
DOVITINIB	3	MUSK
LESTAURTINIB	3	MUSK
RADAFAXINE	2	CHRNB1
GTS-21	2	CHRNB1
DORAMAPIMOD	2	MUSK
FORETINIB	2	MUSK
SU-014813	2	MUSK
DEFOSBARASERTIB	2	MUSK
R-406	2	MUSK
MILREBRUTINIB	2	MUSK
TOZASERTIB	2	MUSK
BMS-754807	2	MUSK
TC-2216	1	CHRNB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
MUSK	247	Binding:247
CHRNB1	87	Binding:51, Functional:36
CHRNE	28	Binding:26, Functional:2
GFPT1	8	Binding:8
CHAT	7	Binding:7
RAPSN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CHAT	2.3.1.6	choline O-acetyltransferase
GFPT1	2.6.1.16	glutamine-fructose-6-phosphate transaminase (isomerizing)
ASL	4.3.2.1	argininosuccinate lyase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MUSK	247

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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)
MECAMYLAMINE	4	CHRNB1, CHRNE
NICOTINE	4	CHRNB1, CHRNE
DONEPEZIL	4	CHRNE
TACRINE	4	CHRNE
VARENICLINE	4	CHRNB1
TROPISETRON	4	CHRNB1
BUPROPION	4	CHRNB1
FEDRATINIB	4	MUSK
SORAFENIB	4	MUSK
NINTEDANIB	4	MUSK
SUNITINIB	4	MUSK
QUIZARTINIB	4	MUSK
CRIZOTINIB	4	MUSK
COENZYME_A	3	CHAT
DEXMECAMYLAMINE	3	CHRNB1
CYTISINICLINE	3	CHRNB1
LINIFANIB	3	MUSK
DOVITINIB	3	MUSK
LESTAURTINIB	3	MUSK
RADAFAXINE	2	CHRNB1
GTS-21	2	CHRNB1
DORAMAPIMOD	2	MUSK
FORETINIB	2	MUSK
SU-014813	2	MUSK
DEFOSBARASERTIB	2	MUSK
R-406	2	MUSK
MILREBRUTINIB	2	MUSK
TOZASERTIB	2	MUSK
BMS-754807	2	MUSK
TC-2216	1	CHRNB1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CHRNE, CHRNB1, MUSK
B	Phased (≥1) drug, not yet approved	1	CHAT
C	Druggable family + PDB, no drug	2	GFPT1, ASL
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	C17orf107, RAPSN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
C17orf107	0	CHRNE
RAPSN	1	MUSK, CHRNB1
GFPT1	8	—
ASL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.