Central core myopathy

Summary

Central core myopathy (MONDO:0007294) is a disease caused by RYR1 (GenCC Strong), with 9 cohort genes and 3 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (United Kingdom) [Orphanet-validated]
• Causal gene: RYR1 (GenCC Strong)
• Cohort genes: 9
• ClinVar variants: 1,020
• Phenotypes (HPO): 25
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.4	United Kingdom	Validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001374	Congenital hip dislocation	Frequent (30-79%)
HP:0001634	Mitral valve prolapse	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0001763	Pes planus	Frequent (30-79%)
HP:0002047	Malignant hyperthermia	Frequent (30-79%)
HP:0002751	Kyphoscoliosis	Frequent (30-79%)
HP:0002828	Multiple joint contractures	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003388	Easy fatigability	Frequent (30-79%)
HP:0003552	Muscle stiffness	Frequent (30-79%)
HP:0003749	Pelvic girdle muscle weakness	Frequent (30-79%)
HP:0003803	Type 1 muscle fiber predominance	Frequent (30-79%)
HP:0030230	Central core regions in muscle fibers	Frequent (30-79%)
HP:0000602	Ophthalmoplegia	Occasional (5-29%)
HP:0002483	Bulbar signs	Occasional (5-29%)
HP:0003798	Nemaline bodies	Occasional (5-29%)
HP:0040081	Abnormal circulating creatine kinase concentration	Occasional (5-29%)
HP:0040191	Rectus femoris muscle atrophy	Excluded (0%)
HP:0001989	Fetal akinesia sequence	Very rare (<1-4%)
HP:0002643	Neonatal respiratory distress	Very rare (<1-4%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Very rare (<1-4%)
HP:0003236	Elevated circulating creatine kinase concentration	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	central core myopathy
Mondo ID	MONDO:0007294
EFO	EFO:1000855
MeSH	D020512
OMIM	117000
Orphanet	597
DOID	DOID:3529
ICD-11	2065822840
NCIT	C83010
SNOMED CT	43152001
UMLS	C5830701
MedGen	1841337
GARD	0006014
Is cancer (heuristic)	no

Also known as: CCD · central core disease · central CORE disease of muscle · muscle core disease · muscular central core disease · myopathy, central core · myopathy, central fibrillar · neuromuscular disease, congenital, with uniform type 1 Fibre · Shy-Magee syndrome

Data availability: 1,020 ClinVar variants · 5 GenCC gene-disease records · 23 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › myofibrillar myopathy › central core myopathy

Related subtypes (12): myofibrillar myopathy 1, myofibrillar myopathy 3, myofibrillar myopathy 4, myofibrillar myopathy 5, myofibrillar myopathy 6, fatal infantile hypertonic myofibrillar myopathy, myofibrillar myopathy 7, myofibrillar myopathy 8, myofibrillar myopathy 11, myofibrillar myopathy 10, myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, myopathy, myofibrillar, 13, with rimmed vacuoles

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:

314 uncertain significance, 114 conflicting classifications of pathogenicity, 45 likely pathogenic, 28 benign, 22 likely benign, 22 benign/likely benign, 19 pathogenic/likely pathogenic, 17 pathogenic, 11 pathogenic; drug response, 4 likely pathogenic; drug response, 3 uncertain significance; drug response, 1 conflicting classifications of pathogenicity; drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
1120218	NM_000540.2(RYR1):c.[14344G>A;14928C>G]		Pathogenic	criteria provided, single submitter
505719	NM_000398.7(CYB5R3):c.757G>A (p.Val253Met)	CYB5R3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1175194	NM_000540.3(RYR1):c.5915A>T (p.Asn1972Ile)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1253809	NM_000540.3(RYR1):c.8310+1G>T	RYR1	Pathogenic	reviewed by expert panel
12964	NM_000540.3(RYR1):c.1840C>T (p.Arg614Cys)	RYR1	Pathogenic; drug response	reviewed by expert panel
12966	NM_000540.3(RYR1):c.7304G>A (p.Arg2435His)	RYR1	Pathogenic; drug response	reviewed by expert panel
12967	NM_000540.3(RYR1):c.487C>T (p.Arg163Cys)	RYR1	Pathogenic; drug response	reviewed by expert panel
12970	NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg)	RYR1	Pathogenic; drug response	reviewed by expert panel
12973	NM_000540.3(RYR1):c.6487C>T (p.Arg2163Cys)	RYR1	Pathogenic; drug response	reviewed by expert panel
12974	NM_000540.3(RYR1):c.6488G>A (p.Arg2163His)	RYR1	Pathogenic; drug response	reviewed by expert panel
12976	NM_000540.3(RYR1):c.6502G>A (p.Val2168Met)	RYR1	Pathogenic; drug response	reviewed by expert panel
12977	NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met)	RYR1	Pathogenic	reviewed by expert panel
12981	NM_000540.3(RYR1):c.12640_12648del (p.Arg4214_Phe4216del)	RYR1	Pathogenic	no assertion criteria provided
12986	NM_000540.3(RYR1):c.14587_14607del (p.Phe4863_Asp4869del)	RYR1	Pathogenic	no assertion criteria provided
12992	NM_000540.3(RYR1):c.13909A>G (p.Thr4637Ala)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12996	NM_000540.3(RYR1):c.13013_13032del (p.Ala4338fs)	RYR1	Pathogenic	reviewed by expert panel
132994	NM_000540.3(RYR1):c.10348-6C>G	RYR1	Pathogenic	reviewed by expert panel
133061	NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln)	RYR1	Pathogenic	reviewed by expert panel
133098	NM_000540.3(RYR1):c.14918C>T (p.Pro4973Leu)	RYR1	Pathogenic/Likely pathogenic	reviewed by expert panel
133102	NM_000540.3(RYR1):c.1597C>T (p.Arg533Cys)	RYR1	Pathogenic; drug response	reviewed by expert panel
133108	NM_000540.3(RYR1):c.1841G>T (p.Arg614Leu)	RYR1	Pathogenic; drug response	reviewed by expert panel
133174	NM_000540.3(RYR1):c.7007G>A (p.Arg2336His)	RYR1	Pathogenic; drug response	reviewed by expert panel
133183	NM_000540.3(RYR1):c.7063C>T (p.Arg2355Trp)	RYR1	Pathogenic; drug response	reviewed by expert panel
1341373	NM_000540.3(RYR1):c.14811C>G (p.Ile4937Met)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1431756	NM_000540.3(RYR1):c.4674dup (p.Asn1559fs)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451182	NM_000540.3(RYR1):c.14569T>C (p.Phe4857Leu)	RYR1	Pathogenic	criteria provided, multiple submitters, no conflicts
1454292	NM_000540.3(RYR1):c.14130-2A>G	RYR1	Pathogenic	criteria provided, multiple submitters, no conflicts
1702862	NM_000540.3(RYR1):c.9345del (p.Ser3116fs)	RYR1	Pathogenic	criteria provided, single submitter
1709010	NM_000540.3(RYR1):c.6811_6836del (p.Thr2271fs)	RYR1	Pathogenic	criteria provided, single submitter
199203	NM_000540.3(RYR1):c.12499G>T (p.Glu4167Ter)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 31 · 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
RYR1	Definitive	Autosomal dominant	RYR1-related myopathy	22

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
ACTN2	Orphanet:154	Familial isolated dilated cardiomyopathy
ACTN2	Orphanet:708129	Autosomal recessive ACTN2-related distal myopathy
ACTN2	Orphanet:708133	Autosomal dominant ACTN2-related distal myopathy
CLN8	Orphanet:1947	Northern epilepsy
CLN8	Orphanet:700484	Late infantile CLN8 disease
ANTXR2	Orphanet:2028	Juvenile hyaline fibromatosis
ANTXR2	Orphanet:2176	Infantile systemic hyalinosis
CRX	Orphanet:1872	Cone rod dystrophy
CRX	Orphanet:65	Leber congenital amaurosis
CRX	Orphanet:791	Retinitis pigmentosa
CYB5R3	Orphanet:621	Autosomal recessive methemoglobinemia
MEFV	Orphanet:117	Behçet disease
MEFV	Orphanet:3243	Sweet syndrome
MEFV	Orphanet:329967	Intermittent hydrarthrosis
MEFV	Orphanet:342	Familial Mediterranean fever
PPT1	Orphanet:699718	Infantile CLN1 disease
PPT1	Orphanet:699734	Late infantile CLN1 disease
PPT1	Orphanet:699739	Juvenile CLN1 disease
PPT1	Orphanet:699745	Adult CLN1 disease

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	gencc,clinvar
ACTN2	HGNC:164	ENSG00000077522	P35609	Alpha-actinin-2	clinvar
CLN8	HGNC:2079	ENSG00000182372	Q9UBY8	Protein CLN8	clinvar
ANTXR2	HGNC:21732	ENSG00000163297	P58335	Anthrax toxin receptor 2	clinvar
CRX	HGNC:2383	ENSG00000105392	O43186	Cone-rod homeobox protein	clinvar
ATP13A4	HGNC:25422	ENSG00000127249	Q4VNC1	Probable cation-transporting ATPase 13A4	clinvar
CYB5R3	HGNC:2873	ENSG00000100243	P00387	NADH-cytochrome b5 reductase 3	clinvar
MEFV	HGNC:6998	ENSG00000103313	O15553	Pyrin	clinvar
PPT1	HGNC:9325	ENSG00000131238	P50897	Palmitoyl-protein thioesterase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
ACTN2	Alpha-actinin-2	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.
CLN8	Protein CLN8	Could play a role in cell proliferation during neuronal differentiation and in protection against cell death.
ANTXR2	Anthrax toxin receptor 2	Necessary for cellular interactions with laminin and the extracellular matrix.
CRX	Cone-rod homeobox protein	Transcription factor that binds and transactivates the sequence 5’-TAATC[CA]-3’ which is found upstream of several photoreceptor-specific genes, including the opsin genes.
CYB5R3	NADH-cytochrome b5 reductase 3	Catalyzes the reduction of two molecules of cytochrome b5 using NADH as the electron donor.
MEFV	Pyrin	Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma.
PPT1	Palmitoyl-protein thioesterase 1	Has thioesterase activity against fatty acid thioesters with 14 -18 carbons, including palmitoyl-CoA, S-palmitoyl-N-acetylcysteamine, and palmitoylated proteins.

Protein-family classification

Druggable: 3 · Difficult: 3 · Unknown: 3 · Druggable fraction: 0.33

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	1	12.4×	0.170
Transcription factor	3	2.8×	0.170
Enzyme (other)	2	2.7×	0.226
Other/Unknown	3	0.6×	0.955

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
ACTN2	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
CLN8	Other/Unknown	no		TLC-dom, TLCD
ANTXR2	Other/Unknown	no		VWF_A, Anthrax_toxin_rcpt_C, Anthrax_toxin_rcpt_extracel
CRX	Transcription factor	no		HD, Homeodomain-like_sf, Otx_TF_C
ATP13A4	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_TPase_V
CYB5R3	Enzyme (other)	yes	1.6.2.2	OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase, CBR-like
MEFV	Transcription factor	no		Znf_B-box, B30.2/SPRY, SPRY_dom
PPT1	Enzyme (other)	yes	3.1.2.2	Palm_thioest, AB_hydrolase_fold

Expression context

Cohort genes with no expression data: 0.

9 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	2
monocyte	2
mononuclear cell	2
gastrocnemius	1
gluteal muscle	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
C1 segment of cervical spinal cord	1
corpus callosum	1
stromal cell of endometrium	1
decidua	1
mucosa of stomach	1
smooth muscle tissue	1
pigmented layer of retina	1
primordial germ cell in gonad	1
retina	1
left lobe of thyroid gland	1
pancreatic ductal cell	1
right lobe of thyroid gland	1
descending thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
ACTN2	226	broad	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle
CLN8	134	ubiquitous	marker	corpus callosum, C1 segment of cervical spinal cord, stromal cell of endometrium
ANTXR2	243	ubiquitous	marker	mucosa of stomach, decidua, smooth muscle tissue
CRX	54	tissue_specific	marker	pigmented layer of retina, retina, primordial germ cell in gonad
ATP13A4	220	broad	marker	pancreatic ductal cell, right lobe of thyroid gland, left lobe of thyroid gland
CYB5R3	294	ubiquitous	marker	right coronary artery, descending thoracic aorta, thoracic aorta
MEFV	153	broad	marker	buccal mucosa cell, monocyte, mononuclear cell
PPT1	294	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTN2	2,781
CYB5R3	2,715
PPT1	2,444
MEFV	2,217
RYR1	2,177
CRX	2,076
ANTXR2	1,270
ATP13A4	1,259
CLN8	1,122

Intra-cohort edges

A	B	Sources
CLN8	PPT1	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTN2	P35609	16
ANTXR2	P58335	14
MEFV	O15553	11
CYB5R3	P00387	5
RYR1	P21817	2
CRX	O43186	1
PPT1	P50897	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLN8	Q9UBY8	90.47
ATP13A4	Q4VNC1	80.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 9 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Vitamin C (ascorbate) metabolism	1	203.9×	0.054	CYB5R3
Inflammasomes	1	163.1×	0.054	MEFV
Cell recruitment (pro-inflammatory response)	1	163.1×	0.054	MEFV
Uptake and function of anthrax toxins	1	135.9×	0.054	ANTXR2
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1	125.5×	0.054	ACTN2
The NLRP3 inflammasome	1	96.0×	0.054	MEFV
Ras activation upon Ca2+ influx through NMDA receptor	1	81.6×	0.054	ACTN2
Unblocking of NMDA receptors, glutamate binding and activation	1	77.7×	0.054	ACTN2
Negative regulation of NMDA receptor-mediated neuronal transmission	1	77.7×	0.054	ACTN2
Nephrin family interactions	1	68.0×	0.054	ACTN2
Long-term potentiation	1	68.0×	0.054	ACTN2
Fatty acyl-CoA biosynthesis	1	62.8×	0.054	PPT1
Purinergic signaling in leishmaniasis infection	1	60.4×	0.054	MEFV
Ion channel transport	2	27.4×	0.054	RYR1, ATP13A4
Muscle contraction	2	22.1×	0.054	RYR1, ACTN2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	51.0×	0.060	MEFV
Striated Muscle Contraction	1	44.1×	0.065	ACTN2
Assembly and cell surface presentation of NMDA receptors	1	36.2×	0.069	ACTN2
Phase I - Functionalization of compounds	1	31.4×	0.069	CYB5R3
Ion transport by P-type ATPases	1	29.7×	0.069	ATP13A4
Post NMDA receptor activation events	1	29.1×	0.069	ACTN2
Ion homeostasis	1	29.1×	0.069	RYR1
Innate Immune System	2	7.3×	0.069	CYB5R3, MEFV
Transport of small molecules	2	7.2×	0.069	RYR1, ATP13A4
Activation of NMDA receptors and postsynaptic events	1	26.3×	0.071	ACTN2
Metabolism of water-soluble vitamins and cofactors	1	25.9×	0.071	CYB5R3
Response to elevated platelet cytosolic Ca2+	1	23.3×	0.071	ACTN2
Leishmania infection	1	23.3×	0.071	MEFV
Parasitic Infection Pathways	1	23.3×	0.071	MEFV
Cell-Cell communication	1	19.7×	0.078	ACTN2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
associative learning	2	107.0×	0.009	CLN8, PPT1
visual perception	3	26.5×	0.009	CLN8, CRX, PPT1
actin filament uncapping	1	1872.4×	0.013	ACTN2
glutamate reuptake	1	936.2×	0.013	CLN8
retinal rod cell apoptotic process	1	936.2×	0.013	CLN8
pyroptosome complex assembly	1	936.2×	0.013	MEFV
retina development in camera-type eye	2	56.7×	0.013	CLN8, CRX
protein catabolic process	2	52.7×	0.013	CLN8, PPT1
nervous system development	3	15.3×	0.013	CLN8, CRX, PPT1
somatic motor neuron differentiation	1	624.1×	0.015	CLN8
negative regulation of macrophage inflammatory protein 1 alpha production	1	624.1×	0.015	MEFV
phospholipase C-activating angiotensin-activated signaling pathway	1	624.1×	0.015	ACTN2
pinocytosis	1	468.1×	0.015	PPT1
microspike assembly	1	468.1×	0.015	ACTN2
polyamine transmembrane transport	1	468.1×	0.015	ATP13A4
membrane raft organization	1	374.5×	0.015	PPT1
negative regulation of toll-like receptor 9 signaling pathway	1	374.5×	0.015	PPT1
positive regulation of pinocytosis	1	374.5×	0.015	PPT1
protein depalmitoylation	1	312.1×	0.015	PPT1
regulation of synapse structure or activity	1	312.1×	0.015	PPT1
musculoskeletal movement	1	312.1×	0.015	CLN8
positive regulation of endocytic recycling	1	312.1×	0.015	ACTN2
negative regulation of neuron apoptotic process	2	24.6×	0.015	CLN8, PPT1
mitochondrial membrane organization	1	267.5×	0.016	CLN8
response to caffeine	1	267.5×	0.016	RYR1
regulation of interleukin-1 beta production	1	234.1×	0.017	MEFV
positive regulation of potassium ion transport	1	234.1×	0.017	ACTN2
negative regulation of potassium ion transport	1	208.1×	0.018	ACTN2
fatty-acyl-CoA biosynthetic process	1	208.1×	0.018	PPT1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	187.2×	0.019	RYR1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 9

Druggability breadth: 5 of 9 evidence-associated genes (56%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RYR1	0	0
ACTN2	0	0
CLN8	0	0
ANTXR2	0	0
CRX	0	0
ATP13A4	0	0
CYB5R3	0	0
MEFV	0	0
PPT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CYB5R3	18	Binding:18
RYR1	16	Binding:13, Functional:3
PPT1	5	Binding:5
ANTXR2	3	Binding:3
MEFV	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYB5R3	1.6.2.2	cytochrome-b5 reductase
PPT1	3.1.2.2, 3.1.2.22	palmitoyl-CoA hydrolase, palmitoyl[protein] hydrolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

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	3	RYR1, CYB5R3, PPT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	ACTN2, CLN8, ANTXR2, CRX, ATP13A4, MEFV

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RYR1	16	—
ACTN2	0	—
CLN8	0	—
ANTXR2	3	—
CRX	0	—
ATP13A4	0	—
CYB5R3	18	—
MEFV	1	—
PPT1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00272883	Not specified	RECRUITING	Molecular and Genetic Studies of Congenital Myopathies
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