Centronuclear myopathy

disease

On this page

Also known as CNMmyopathy, centronuclearmyopathy, myotubular

Summary

Centronuclear myopathy (MONDO:0018947) is a disease (an umbrella term covering 5 Mondo subtypes) with 20 cohort genes and 12 clinical trials. The dominant Reactome pathway is Striated Muscle Contraction (3 cohort genes).

At a glance

Prevalence: Unknown (Worldwide) [Orphanet-validated]
Umbrella term: 5 Mondo subtypes
Cohort genes: 20
ClinVar variants: 121
Clinical trials: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	centronuclear myopathy
Mondo ID	MONDO:0018947
OMIM	160150
Orphanet	595
DOID	DOID:14717
ICD-10-CM	G71.22
ICD-11	742097637
SNOMED CT	82077006
UMLS	C0175709
MedGen	104495
GARD	0000101
NORD	909
Is cancer (heuristic)	no

Also known as: centronuclear myopathy · CNM · myopathy, centronuclear · myopathy, myotubular

Data availability: 121 ClinVar variants · 35 ClinGen variant curations · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › centronuclear myopathy

Subtypes (5): autosomal dominant centronuclear myopathy, X-linked myotubular myopathy, congenital myopathy with internal nuclei and atypical cores, autosomal recessive centronuclear myopathy, myopathy, centronuclear, 6, with fiber-type disproportion

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

121 retrieved; paginated sample, class counts are floors:

32 pathogenic, 27 conflicting classifications of pathogenicity, 21 likely pathogenic, 20 pathogenic/likely pathogenic, 10 benign, 8 uncertain significance, 1 drug response, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
801335	NM_001198800.3(ASCC1):c.328C>T (p.Arg110Ter)	ASCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2061561	NM_000069.3(CACNA1S):c.4967del (p.Leu1656fs)	CACNA1S	Pathogenic	criteria provided, multiple submitters, no conflicts
2443900	NM_000069.3(CACNA1S):c.1189_1190del (p.Ser397fs)	CACNA1S	Pathogenic	criteria provided, multiple submitters, no conflicts
2443904	NM_000069.3(CACNA1S):c.2225C>A (p.Pro742Gln)	CACNA1S	Pathogenic	criteria provided, single submitter
449923	NM_000079.4(CHRNA1):c.1321G>A (p.Gly441Arg)	CHRNA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158514	NM_001005361.3(DNM2):c.1565G>A (p.Arg522His)	DNM2	Pathogenic	reviewed by expert panel
158519	NM_001005361.3(DNM2):c.1862T>C (p.Leu621Pro)	DNM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158520	NM_001005361.3(DNM2):c.1880C>G (p.Pro627Arg)	DNM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449326	NM_001005361.3(DNM2):c.1852G>A (p.Ala618Thr)	DNM2	Pathogenic	reviewed by expert panel
7279	NM_001005361.3(DNM2):c.1106G>A (p.Arg369Gln)	DNM2	Pathogenic	reviewed by expert panel
7280	NM_001005361.3(DNM2):c.1105C>T (p.Arg369Trp)	DNM2	Pathogenic	reviewed by expert panel
7281	NM_001005361.3(DNM2):c.1393C>T (p.Arg465Trp)	DNM2	Pathogenic	reviewed by expert panel
7282	NM_001005361.3(DNM2):c.1102G>A (p.Glu368Lys)	DNM2	Pathogenic	reviewed by expert panel
7285	NM_001005361.3(DNM2):c.1856C>T (p.Ser619Leu)	DNM2	Pathogenic	reviewed by expert panel
11551	NM_001159699.2(FHL1):c.443G>T (p.Cys148Phe)	FHL1	Pathogenic	criteria provided, single submitter
3233258	NM_014009.4(FOXP3):c.116_122dup (p.Gly43fs)	FOXP3	Pathogenic	criteria provided, single submitter
3233244	NM_015602.4(TOR1AIP1):c.63dup (p.Arg22fs)	LOC112577517	Pathogenic	criteria provided, single submitter
590611	NM_000540.3(RYR1):c.8342_8343del (p.Ile2781fs)	LOC126862902	Pathogenic	criteria provided, multiple submitters, no conflicts
446158	NM_016653.3(MAP3K20):c.490_491del (p.Met164fs)	MAP3K20	Pathogenic	criteria provided, single submitter
11055	NM_000252.3(MTM1):c.205C>T (p.Arg69Cys)	MTM1	Pathogenic	reviewed by expert panel
11057	NM_000252.3(MTM1):c.141_144del	MTM1	Pathogenic	reviewed by expert panel
11058	NM_000252.3(MTM1):c.1261-10A>G	MTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11060	NM_000252.3(MTM1):c.670C>T (p.Arg224Ter)	MTM1	Pathogenic	reviewed by expert panel
158913	NM_000252.3(MTM1):c.1261C>T (p.Arg421Ter)	MTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
158914	NM_000252.3(MTM1):c.1262G>A (p.Arg421Gln)	MTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158978	NM_000252.3(MTM1):c.535C>T (p.Pro179Ser)	MTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
158987	NM_000252.3(MTM1):c.614C>T (p.Pro205Leu)	MTM1	Pathogenic	reviewed by expert panel
211525	NM_000252.3(MTM1):c.1089dup (p.Val364fs)	MTM1	Pathogenic	criteria provided, single submitter
530855	NM_000252.3(MTM1):c.1210G>A (p.Glu404Lys)	MTM1	Pathogenic	reviewed by expert panel
5091	NM_130837.3(OPA1):c.1499G>A (p.Arg500His)	OPA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 75 · 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
MYF6	Limited	Autosomal dominant	centronuclear myopathy

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYF6	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1
TPM3	Orphanet:171433	Intermediate nemaline myopathy
TPM3	Orphanet:171439	Childhood-onset nemaline myopathy
TPM3	Orphanet:171881	Cap myopathy
TPM3	Orphanet:178342	Inflammatory myofibroblastic tumor
TPM3	Orphanet:2020	Congenital fiber-type disproportion myopathy
TPM3	Orphanet:476406	Congenital generalized hypercontractile muscle stiffness syndrome
TRIP4	Orphanet:486811	Prenatal-onset spinal muscular atrophy with congenital bone fractures
TRIP4	Orphanet:486815	Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
ACTA1	Orphanet:171430	Severe congenital nemaline myopathy
ACTA1	Orphanet:171433	Intermediate nemaline myopathy
ACTA1	Orphanet:171436	Typical nemaline myopathy
ACTA1	Orphanet:171439	Childhood-onset nemaline myopathy
ACTA1	Orphanet:2020	Congenital fiber-type disproportion myopathy
ACTA1	Orphanet:447977	Progressive scapulohumeroperoneal distal myopathy
ACTA1	Orphanet:97240	Zebra body myopathy
ACTA1	Orphanet:97244	Rigid spine syndrome
ACTA1	Orphanet:98904	Congenital myopathy with excess of thin filaments
CACNA1S	Orphanet:397755	Periodic paralysis with transient compartment-like syndrome
CACNA1S	Orphanet:423	Malignant hyperthermia of anesthesia

Cohort genes → proteins

20 cohort genes, 19 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	20

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYF6	HGNC:7566	ENSG00000111046	P23409	Myogenic factor 6	gencc
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	clinvar
TPM3	HGNC:12012	ENSG00000143549	P06753	Tropomyosin alpha-3 chain	clinvar
TRIP4	HGNC:12310	ENSG00000103671	Q15650	Activating signal cointegrator 1	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
ACTA1	HGNC:129	ENSG00000143632	P68133	Actin, alpha skeletal muscle	clinvar
CACNA1S	HGNC:1397	ENSG00000081248	Q13698	Voltage-dependent L-type calcium channel subunit alpha-1S	clinvar
CCDC78	HGNC:14153	ENSG00000162004	A2IDD5	Coiled-coil domain-containing protein 78	clinvar
MAP3K20	HGNC:17797	ENSG00000091436	Q9NYL2	Mitogen-activated protein kinase kinase kinase 20	clinvar
CFL2	HGNC:1875	ENSG00000165410	Q9Y281	Cofilin-2	clinvar
CHRNA1	HGNC:1955	ENSG00000138435	P02708	Acetylcholine receptor subunit alpha	clinvar
CHRND	HGNC:1965	ENSG00000135902	Q07001	Acetylcholine receptor subunit delta	clinvar
ASCC1	HGNC:24268	ENSG00000138303	Q8N9N2	Activating signal cointegrator 1 complex subunit 1	clinvar
DNM2	HGNC:2974	ENSG00000079805	P50570	Dynamin-2	clinvar
FHL1	HGNC:3702	ENSG00000022267	Q13642	Four and a half LIM domains protein 1	clinvar
TTN-AS1	HGNC:44124	ENSG00000237298		TTN antisense RNA 1	clinvar
FOXP3	HGNC:6106	ENSG00000049768	Q9BZS1	Forkhead box protein P3	clinvar
MTM1	HGNC:7448	ENSG00000171100	Q13496	Myotubularin	clinvar
OPA1	HGNC:8140	ENSG00000198836	O60313	Dynamin-like GTPase OPA1, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYF6	Myogenic factor 6	Involved in muscle differentiation (myogenic factor).
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
TPM3	Tropomyosin alpha-3 chain	Binds to actin filaments in muscle and non-muscle cells.
TRIP4	Activating signal cointegrator 1	Transcription coactivator which associates with nuclear receptors, transcriptional coactivators including EP300, CREBBP and NCOA1, and basal transcription factors like TBP and TFIIA to facilitate nuclear receptors-mediated transcription.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
ACTA1	Actin, alpha skeletal muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
CACNA1S	Voltage-dependent L-type calcium channel subunit alpha-1S	Pore-forming, alpha-1S subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle.
CCDC78	Coiled-coil domain-containing protein 78	Component of the deuterosome, a structure that promotes de novo centriole amplification in multiciliated cells that can generate more than 100 centrioles.
MAP3K20	Mitogen-activated protein kinase kinase kinase 20	Stress-activated component of a protein kinase signal transduction cascade that promotes programmed cell death in response to various stress, such as ribosomal stress, osmotic shock and ionizing radiation.
CFL2	Cofilin-2	Controls reversibly actin polymerization and depolymerization in a pH-sensitive manner.
CHRNA1	Acetylcholine receptor subunit alpha	Upon acetylcholine binding, 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.
CHRND	Acetylcholine receptor subunit delta	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.
ASCC1	Activating signal cointegrator 1 complex subunit 1	Plays a role in DNA damage repair as component of the ASCC complex.
DNM2	Dynamin-2	Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission at plasma membrane during endocytosis and filament remodeling at many actin structures during organization of the actin cytoskeleton.
FHL1	Four and a half LIM domains protein 1	May have an involvement in muscle development or hypertrophy.
FOXP3	Forkhead box protein P3	Transcriptional regulator which is crucial for the development and inhibitory function of regulatory T-cells (Treg).
MTM1	Myotubularin	Lipid phosphatase which dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2).
OPA1	Dynamin-like GTPase OPA1, mitochondrial	Dynamin-related GTPase that is essential for normal mitochondrial morphology by mediating fusion of the mitochondrial inner membranes, regulating cristae morphology and maintaining respiratory chain function.

Protein-family classification

Druggable: 6 · Difficult: 5 · Unknown: 9 · Druggable fraction: 0.3

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	2	11.2×	0.096
Phosphatase	1	4.2×	0.381
Kinase	2	2.8×	0.381
Transcription factor	4	1.6×	0.381
Scaffold/PPI	1	0.9×	0.885
Other/Unknown	9	0.8×	0.885
Enzyme (other)	1	0.6×	0.885

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYF6	Transcription factor	no		MyoD_N, bHLH_dom, HLH_DNA-bd_sf
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
TPM3	Other/Unknown	no		Tropomyosin
TRIP4	Transcription factor	no		ASCH_domain, TRIP4/RQT4_C2HC5_Znf, PUA-like_sf
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
ACTA1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
CACNA1S	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1ssu
CCDC78	Other/Unknown	no		DUF4472, CCDC78
MAP3K20	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, SAM
CFL2	Other/Unknown	no		ADF-H, ADF/Cofilin, ADF-H/Gelsolin-like_dom_sf
CHRNA1	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
CHRND	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
ASCC1	Other/Unknown	no		KH_dom_type_1, Cyclic_Pdiesterase, ASCC1
DNM2	Scaffold/PPI	no	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, PH_domain
FHL1	Transcription factor	no		Znf_LIM, Fhl1, LIM_FHL1/2/3/5_N
TTN-AS1	Other/Unknown	no
FOXP3	Transcription factor	no		Fork_head_dom, Znf_C2H2_type, TF_fork_head_CS_2
MTM1	Phosphatase	yes	3.1.3.64	Tyr_Pase_dom, Tyr_Pase_cat, GRAM
OPA1	Enzyme (other)	yes	3.6.5.5	Dynamin_GTPase, Dynamin, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

19 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)	20
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gluteal muscle	6
skeletal muscle tissue of rectus abdominis	5
hindlimb stylopod muscle	5
gastrocnemius	4
biceps brachii	3
skeletal muscle tissue of biceps brachii	3
triceps brachii	2
diaphragm	2
muscle of leg	2
calcaneal tendon	2
left ovary	1
right adrenal gland	1
right adrenal gland cortex	1
amniotic fluid	1
lower esophagus mucosa	1
sural nerve	1
bronchial epithelial cell	1
bronchus	1
right uterine tube	1
heart right ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYF6	137	tissue_specific	marker	gluteal muscle, skeletal muscle tissue of rectus abdominis, triceps brachii
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
TPM3	243	ubiquitous	marker	diaphragm, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
TRIP4	282	ubiquitous	marker	sural nerve, lower esophagus mucosa, amniotic fluid
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
ACTA1	203	broad	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
CACNA1S	105	tissue_specific	marker	gluteal muscle, hindlimb stylopod muscle, triceps brachii
CCDC78	176	broad	marker	right uterine tube, bronchial epithelial cell, bronchus
MAP3K20	267	ubiquitous	marker	heart right ventricle, skeletal muscle tissue of rectus abdominis, biceps brachii
CFL2	261	ubiquitous	marker	cardiac muscle of right atrium, left ventricle myocardium, tibialis anterior
CHRNA1	149	broad	marker	gastrocnemius, gluteal muscle, muscle of leg
CHRND	86	tissue_specific	yes	gastrocnemius, muscle of leg, hindlimb stylopod muscle
ASCC1	282	ubiquitous	marker	calcaneal tendon, ventricular zone, sperm
DNM2	234	ubiquitous	marker	metanephros cortex, granulocyte, mucosa of transverse colon
FHL1	291	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, skeletal muscle tissue of biceps brachii
TTN-AS1	174	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, right atrium auricular region
FOXP3	155	tissue_specific	marker	buccal mucosa cell, parotid gland, skeletal muscle tissue of rectus abdominis
MTM1	281	ubiquitous	marker	secondary oocyte, rectum, germinal epithelium of ovary
OPA1	288	ubiquitous	marker	adrenal tissue, calcaneal tendon, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 12.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNM2	4,715
FOXP3	4,306
TTN	4,237
CFL2	4,226
TPM3	4,099
MED12	3,322
OPA1	2,630
RYR1	2,177
CACNA1S	1,818
MAP3K20	1,615

Intra-cohort edges

A	B	Sources
ACTA1	CCDC78	biogrid_interaction
ASCC1	TRIP4	biogrid_interaction, intact, string_interaction
CACNA1S	MTM1	string_interaction
CACNA1S	RYR1	string_interaction
CCDC78	DNM2	string_interaction
CCDC78	MTM1	string_interaction
CCDC78	RYR1	string_interaction
CHRNA1	CHRND	biogrid_interaction, string_interaction
DNM2	MTM1	string_interaction
FHL1	TTN	biogrid_interaction, string_interaction
MTM1	RYR1	string_interaction
RYR1	TTN	intact

Structural data

PDB: 16 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
CHRNA1	P02708	15
CHRND	Q07001	13
CFL2	Q9Y281	11
OPA1	O60313	11
TRIP4	Q15650	10
MAP3K20	Q9NYL2	8
ACTA1	P68133	5
FHL1	Q13642	4
MED12	Q93074	3
RYR1	P21817	2
CACNA1S	Q13698	2
FOXP3	Q9BZS1	2
TPM3	P06753	1
ASCC1	Q8N9N2	1
DNM2	P50570	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTM1	Q13496	90.10
MYF6	P23409	67.22
CCDC78	A2IDD5	66.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 80. Enrichment computed across 20 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	3	61.7×	0.001	TPM3, TTN, ACTA1
Presynaptic nicotinic acetylcholine receptors	2	126.9×	0.003	CHRNA1, CHRND
Acetylcholine binding and downstream events	2	108.8×	0.003	CHRNA1, CHRND
Postsynaptic nicotinic acetylcholine receptors	2	108.8×	0.003	CHRNA1, CHRND
ALKBH3 mediated reversal of alkylation damage	1	190.3×	0.061	ASCC1
NOSTRIN mediated eNOS trafficking	1	152.3×	0.061	DNM2
Regulation of Apoptosis	1	126.9×	0.061	OPA1
RUNX1 regulates transcription of genes involved in WNT signaling	1	126.9×	0.061	FOXP3
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	1	108.8×	0.061	CHRND
DNA Damage Reversal	1	108.8×	0.061	ASCC1
Reversal of alkylation damage by DNA dioxygenases	1	108.8×	0.061	ASCC1
Highly calcium permeable nicotinic acetylcholine receptors	1	84.6×	0.061	CHRNA1
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	1	76.1×	0.061	FOXP3
Formation of annular gap junctions	1	69.2×	0.061	DNM2
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	69.2×	0.061	CHRNA1
Synthesis of PIPs at the late endosome membrane	1	63.4×	0.061	MTM1
Gap junction degradation	1	63.4×	0.061	DNM2
Regulation of CDH1 Function	1	63.4×	0.061	ACTA1
Neurotransmitter receptors and postsynaptic signal transmission	2	13.4×	0.061	CHRNA1, CHRND
Muscle contraction	2	10.3×	0.061	RYR1, ACTA1
Transmission across Chemical Synapses	2	10.2×	0.061	CHRNA1, CHRND
Retrograde neurotrophin signalling	1	54.4×	0.066	DNM2
Synthesis of PIPs at the early endosome membrane	1	47.6×	0.072	MTM1
TGFBR3 expression	1	30.4×	0.108	MYF6
Myogenesis	1	25.4×	0.122	MYF6
Signaling by TGFBR3	1	24.6×	0.122	MYF6
PI Metabolism	1	23.8×	0.122	MTM1
Lysosome Vesicle Biogenesis	1	21.8×	0.124	DNM2
Neuronal System	2	5.9×	0.124	CHRNA1, CHRND
Formation of the dystrophin-glycoprotein complex (DGC)	1	20.6×	0.127	ACTA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
muscle contraction	6	65.7×	6e-08	RYR1, TPM3, TTN, ACTA1, CACNA1S, CHRND
skeletal muscle tissue growth	3	443.5×	3e-06	CHRNA1, CHRND, MTM1
skeletal muscle contraction	4	107.5×	4e-06	TTN, CCDC78, CHRNA1, CHRND
striated muscle contraction	3	133.0×	8e-05	RYR1, TTN, CACNA1S
membrane tubulation	2	591.3×	1e-04	DNM2, OPA1
muscle cell cellular homeostasis	3	102.3×	1e-04	CFL2, CHRNA1, MTM1
skeletal muscle fiber development	3	85.8×	2e-04	RYR1, ACTA1, CACNA1S
skeletal muscle thin filament assembly	2	295.6×	5e-04	TTN, ACTA1
musculoskeletal movement	2	295.6×	5e-04	CHRNA1, CHRND
cellular response to caffeine	2	161.3×	0.002	RYR1, CACNA1S
acetylcholine receptor signaling pathway	2	65.7×	0.009	CHRNA1, CHRND
neuromuscular junction development	2	55.4×	0.011	CACNA1S, CHRNA1
neuromuscular process	2	55.4×	0.011	CHRNA1, CHRND
membrane depolarization	2	53.8×	0.011	CHRNA1, CHRND
positive regulation of peripheral T cell tolerance induction	1	887.0×	0.013	FOXP3
skeletal muscle adaptation	1	887.0×	0.013	CACNA1S
regulation of vacuole organization	1	887.0×	0.013	MTM1
negative regulation of stress-activated protein kinase signaling cascade	1	887.0×	0.013	MAP3K20
positive regulation of mitotic DNA damage checkpoint	1	887.0×	0.013	MAP3K20
mitochondrial inner membrane fusion	1	887.0×	0.013	OPA1
sarcomere organization	2	40.3×	0.013	TTN, CFL2
release of sequestered calcium ion into cytosol	2	36.2×	0.015	RYR1, CACNA1S
skeletal muscle tissue development	2	30.6×	0.020	CFL2, MYF6
CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment	1	443.5×	0.020	FOXP3
establishment of endothelial blood-brain barrier	1	443.5×	0.020	FOXP3
vesicle scission	1	443.5×	0.020	DNM2
negative regulation of membrane tubulation	1	443.5×	0.020	DNM2
negative regulation of chronic inflammatory response	1	295.6×	0.022	FOXP3
skeletal muscle myosin thick filament assembly	1	295.6×	0.022	TTN
transforming growth factor beta1 production	1	295.6×	0.022	FOXP3

Therapeutics

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 6 · Undrugged: 14

Druggability breadth: 11 of 20 evidence-associated genes (55%) 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
CACNA1S	BEPRIDIL
MAP3K20	PONATINIB
CHRNA1	VARENICLINE
CHRND	VARENICLINE
OPA1	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP3K20	53	4
CACNA1S	48	4
CHRNA1	12	4
CHRND	10	4
OPA1	2	4
MED12	1	2
MYF6	0	0
RYR1	0	0
TPM3	0	0
TRIP4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1S
IMIPRAMINE	4	CACNA1S
HALOFANTRINE	4	CACNA1S
DROPERIDOL	4	CACNA1S
SAQUINAVIR	4	CACNA1S
DULOXETINE	4	CACNA1S
DIAZEPAM	4	CACNA1S
SERTINDOLE	4	CACNA1S
QUINIDINE	4	CACNA1S
LAMIVUDINE	4	CACNA1S
PIMOZIDE	4	CACNA1S
PHENYTOIN	4	CACNA1S
TERFENADINE	4	CACNA1S
CISAPRIDE	4	CACNA1S
SOLIFENACIN	4	CACNA1S
NIFEDIPINE	4	CACNA1S
DILTIAZEM	4	CACNA1S
NILOTINIB	4	CACNA1S, MAP3K20
ASTEMIZOLE	4	CACNA1S
TERODILINE	4	CACNA1S
CLOZAPINE	4	CACNA1S
MIBEFRADIL	4	CACNA1S
DOFETILIDE	4	CACNA1S
THIORIDAZINE	4	CACNA1S
PAROXETINE	4	CACNA1S
DONEPEZIL	4	CACNA1S
IBUTILIDE	4	CACNA1S
SUNITINIB	4	CACNA1S
HALOPERIDOL	4	CACNA1S
DASATINIB	4	CACNA1S, MAP3K20

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
MAP3K20	245	Binding:244, Functional:1
CACNA1S	228	Binding:142, Functional:79, Toxicity:5, ADMET:2
CHRNA1	157	Binding:107, Functional:47, ADMET:2, Toxicity:1
CHRND	75	Binding:44, Functional:31
TPM3	18	Binding:18
RYR1	16	Binding:13, Functional:3
DNM2	15	Binding:15
MED12	6	Binding:6
FOXP3	4	Binding:4
OPA1	2	Binding:2
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase
DNM2	3.6.5.5	dynamin GTPase
MTM1	3.1.3.64, 3.1.3.95	phosphatidylinositol-3-phosphatase, phosphatidylinositol-3,5-bisphosphate 3-phosphatase
OPA1	3.6.5.5	dynamin GTPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1S	228
MAP3K20	245
CHRNA1	157

Pharmacogenomics

Cohort genes with a PharmGKB record: 19; with CPIC/DPWG dosing guidelines: 2.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1
CACNA1S	1

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)
BEPRIDIL	4	CACNA1S
IMIPRAMINE	4	CACNA1S
HALOFANTRINE	4	CACNA1S
DROPERIDOL	4	CACNA1S
SAQUINAVIR	4	CACNA1S
DULOXETINE	4	CACNA1S
DIAZEPAM	4	CACNA1S
SERTINDOLE	4	CACNA1S
QUINIDINE	4	CACNA1S
LAMIVUDINE	4	CACNA1S
PIMOZIDE	4	CACNA1S
PHENYTOIN	4	CACNA1S
TERFENADINE	4	CACNA1S
CISAPRIDE	4	CACNA1S
SOLIFENACIN	4	CACNA1S
NIFEDIPINE	4	CACNA1S
DILTIAZEM	4	CACNA1S
NILOTINIB	4	CACNA1S, MAP3K20
ASTEMIZOLE	4	CACNA1S
TERODILINE	4	CACNA1S
CLOZAPINE	4	CACNA1S
MIBEFRADIL	4	CACNA1S
DOFETILIDE	4	CACNA1S
THIORIDAZINE	4	CACNA1S
PAROXETINE	4	CACNA1S
DONEPEZIL	4	CACNA1S
IBUTILIDE	4	CACNA1S
SUNITINIB	4	CACNA1S
HALOPERIDOL	4	CACNA1S
DASATINIB	4	CACNA1S, MAP3K20

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	CACNA1S, MAP3K20, CHRNA1, CHRND, OPA1
B	Phased (≥1) drug, not yet approved	1	MED12
C	Druggable family + PDB, no drug	2	RYR1, TTN
D	Druggable family + AlphaFold only, no drug	1	MTM1
E	Difficult family or no structure, no drug	11	MYF6, TPM3, TRIP4, ACTA1, CCDC78, CFL2, ASCC1, DNM2, FHL1, TTN-AS1 (+1 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MYF6	0	—
RYR1	16	—
TPM3	18	—
TRIP4	0	—
TTN	1	—
ACTA1	0	—
CCDC78	0	—
CFL2	0	—
ASCC1	0	—
DNM2	15	—
FHL1	0	—
TTN-AS1	0	—
FOXP3	4	—
MTM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	10
PHASE1/PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04033159	PHASE1/PHASE2	TERMINATED	Early Phase Human Drug Trial to Investigate Dynamin 101 (DYN101) in Patients ≥ 16 Years With Centronuclear Myopathies
NCT04743557	PHASE1/PHASE2	WITHDRAWN	Early Phase Human Drug Trial to Investigate DYN101 in Participants 2 to 17 Years With Centronuclear Myopathies
NCT00272883	Not specified	RECRUITING	Molecular and Genetic Studies of Congenital Myopathies
NCT04064307	Not specified	RECRUITING	Myotubular and Centronuclear Myopathy Patient Registry
NCT05982119	Not specified	RECRUITING	Assessments in Patients With Muscular Pathology and in Control Subjects : The ActiLiège Next Study
NCT06157268	Not specified	RECRUITING	The Natural History and Muscle Fatigability of Patients With Congenital Myopathies.
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease
NCT07021820	Not specified	RECRUITING	Multispectral Optoacoustic Tomography for Advanced Imaging of Centronuclear Myopathy
NCT07478172	Not specified	RECRUITING	Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease
NCT03351270	Not specified	COMPLETED	Prospective Natural History Study of Patients With Myotubular Myopathy and Other CentroNuclear Myopathies
NCT04977648	Not specified	WITHDRAWN	Natural History Study of Patients With Centronuclear Myopathies
NCT05099107	Not specified	COMPLETED	Changes of Motor Function Tests in Congenital Myopathy Subjects Treated With Oral Salbutamol as Compared to no Treatment

Cohort genes: MYF6, RYR1, MED12, TPM3, TRIP4, TTN, ACTA1, CACNA1S, CCDC78, MAP3K20, CFL2, CHRNA1, CHRND, ASCC1, DNM2, FHL1, TTN-AS1, FOXP3, MTM1, OPA1
Associated genes: BIN1