Malignant hyperthermia, susceptibility to, 1

Summary

Malignant hyperthermia, susceptibility to, 1 (MONDO:0007783) is a disease caused by RYR1 (GenCC Definitive), with 8 cohort genes. The dominant Reactome pathway is Ion homeostasis (3 cohort genes).

At a glance

• Causal gene: RYR1 (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 5,191

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	malignant hyperthermia, susceptibility to, 1
Mondo ID	MONDO:0007783
MeSH	C535694
OMIM	145600
DOID	DOID:0080990
UMLS	C2930980
MedGen	443948
Is cancer (heuristic)	no

Also known as: hyperpyrexia, malignant · hyperpyrexia, malignant;MH KING syndrome, included · hyperthermia of anaesthesia · hyperthermia of anesthesia · King-Denborough syndrome, included · malignant hyperthermia of anaesthesia caused by mutation in RYR1 · malignant hyperthermia of anesthesia caused by mutation in RYR1 · malignant hyperthermia susceptibility 1 · malignant hyperthermia susceptibility type 1 · malignant hyperthermia, susceptibility to, 1 · malignant hyperthermia, susceptibility to, type 1 · MHS · MHS1 · RYR1 malignant hyperthermia of anaesthesia · RYR1 malignant hyperthermia of anesthesia

Data availability: 5,191 ClinVar variants · 211 ClinGen variant curations · 5 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › malignant hyperthermia, susceptibility to › malignant hyperthermia, susceptibility to, 1

Related subtypes (5): malignant hyperthermia, susceptibility to, 2, malignant hyperthermia, susceptibility to, 3, malignant hyperthermia, susceptibility to, 4, malignant hyperthermia, susceptibility to, 5, malignant hyperthermia, susceptibility to, 6

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:

294 uncertain significance, 146 likely benign, 60 conflicting classifications of pathogenicity, 30 likely pathogenic, 20 pathogenic; drug response, 12 benign, 10 benign/likely benign, 10 pathogenic, 10 likely pathogenic; drug response, 3 uncertain significance; drug response, 2 drug response, 1 conflicting classifications of pathogenicity; drug response, 1 risk factor, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
12969	NM_000540.3(RYR1):c.1021G>A (p.Gly341Arg)	RYR1	Pathogenic	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
12978	NM_000540.3(RYR1):c.14477C>T (p.Thr4826Ile)	RYR1	Pathogenic; drug response	reviewed by expert panel
12993	NM_000540.3(RYR1):c.1565A>C (p.Tyr522Ser)	RYR1	Pathogenic; drug response	reviewed by expert panel
132992	NM_000540.3(RYR1):c.1021G>C (p.Gly341Arg)	RYR1	Pathogenic	reviewed by expert panel
132994	NM_000540.3(RYR1):c.10348-6C>G	RYR1	Pathogenic	reviewed by expert panel
132995	NM_000540.3(RYR1):c.103T>C (p.Cys35Arg)	RYR1	Pathogenic; drug response	reviewed by expert panel
133027	NM_000540.3(RYR1):c.11969G>T (p.Gly3990Val)	RYR1	Pathogenic; drug response	reviewed by expert panel
133029	NM_000540.3(RYR1):c.1201C>T (p.Arg401Cys)	RYR1	Pathogenic; drug response	reviewed by expert panel
133030	NM_000540.3(RYR1):c.1202G>A (p.Arg401His)	RYR1	Pathogenic	reviewed by expert panel
133040	NM_000540.3(RYR1):c.12700G>C (p.Val4234Leu)	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
133137	NM_000540.3(RYR1):c.488G>T (p.Arg163Leu)	RYR1	Pathogenic; drug response	reviewed by expert panel
133147	NM_000540.3(RYR1):c.529C>T (p.Arg177Cys)	RYR1	Pathogenic	reviewed by expert panel
133174	NM_000540.3(RYR1):c.7007G>A (p.Arg2336His)	RYR1	Pathogenic; drug response	reviewed by expert panel
133182	NM_000540.3(RYR1):c.7048G>A (p.Ala2350Thr)	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
133189	NM_000540.3(RYR1):c.7124G>C (p.Gly2375Ala)	RYR1	Pathogenic; drug response	reviewed by expert panel
133202	NM_000540.3(RYR1):c.7360C>T (p.Arg2454Cys)	RYR1	Pathogenic; drug response	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 17 · 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	malignant hyperthermia, susceptibility to, 1	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
CACNA1S	Orphanet:397755	Periodic paralysis with transient compartment-like syndrome
CACNA1S	Orphanet:423	Malignant hyperthermia of anesthesia
CACNA1S	Orphanet:681	Hypokalemic periodic paralysis
CACNA1S	Orphanet:79102	Thyrotoxic periodic paralysis
PYGM	Orphanet:368	Glycogen storage disease due to muscle glycogen phosphorylase deficiency

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
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	gencc,clinvar
SLC8A3	HGNC:11070	ENSG00000100678	P57103	Sodium/calcium exchanger 3	clinvar
TRPC1	HGNC:12333	ENSG00000144935	P48995	Short transient receptor potential channel 1	clinvar
CACNA1S	HGNC:1397	ENSG00000081248	Q13698	Voltage-dependent L-type calcium channel subunit alpha-1S	clinvar
CACNG1	HGNC:1405	ENSG00000108878	Q06432	Voltage-dependent calcium channel gamma-1 subunit	clinvar
SYPL2	HGNC:27638	ENSG00000143028	Q5VXT5	Synaptophysin-like protein 2	clinvar
HSP90AA1	HGNC:5253	ENSG00000080824	P07900	Heat shock protein HSP 90-alpha	clinvar
PYGM	HGNC:9726	ENSG00000068976	P11217	Glycogen phosphorylase, muscle form	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.
SLC8A3	Sodium/calcium exchanger 3	Mediates the electrogenic exchange of Ca(2+) against Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes.
TRPC1	Short transient receptor potential channel 1	Forms a receptor-activated non-selective calcium permeant cation channel.
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.
CACNG1	Voltage-dependent calcium channel gamma-1 subunit	Regulatory subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle.
SYPL2	Synaptophysin-like protein 2	Involved in communication between the T-tubular and junctional sarcoplasmic reticulum (SR) membranes.
HSP90AA1	Heat shock protein HSP 90-alpha	Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction.
PYGM	Glycogen phosphorylase, muscle form	Allosteric enzyme that catalyzes the rate-limiting step in glycogen catabolism, the phosphorolytic cleavage of glycogen to produce glucose-1-phosphate, and plays a central role in maintaining cellular and organismal glucose homeostasis.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 4 · 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
Ion channel	3	41.8×	1e-04
Enzyme (other)	1	1.5×	0.753
Other/Unknown	4	0.9×	0.755

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
SLC8A3	Other/Unknown	no		Calx_beta, Na_Ca_Ex, NaCa_Exmemb
TRPC1	Ion channel	yes		Ankyrin_rpt, TRPC_channel, TRPC1_channel
CACNA1S	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1ssu
CACNG1	Other/Unknown	no		PMP22/EMP/MP20/Claudin, VDCC_g1su, VDCC_gsu
SYPL2	Other/Unknown	no		Synaptophysin/porin, Marvel
HSP90AA1	Enzyme (other)	yes	3.6.4.10	Hsp90_fam, HATPase_dom, Heat_shock_protein_90_CS
PYGM	Other/Unknown	no		Glyco_trans_35, Glycg_phsphrylas, Pyridoxal_P_attach_site

Expression context

Cohort genes with no expression data: 0.

7 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
gastrocnemius	5
hindlimb stylopod muscle	4
gluteal muscle	2
triceps brachii	2
cortical plate	1
tibia	1
blood vessel layer	1
buccal mucosa cell	1
germinal epithelium of ovary	1
deltoid	1
tibialis anterior	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
skeletal muscle tissue of biceps brachii	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
SLC8A3	168	broad	marker	tibia, gastrocnemius, cortical plate
TRPC1	265	ubiquitous	marker	germinal epithelium of ovary, blood vessel layer, buccal mucosa cell
CACNA1S	105	tissue_specific	marker	gluteal muscle, hindlimb stylopod muscle, triceps brachii
CACNG1	124	tissue_specific	marker	gastrocnemius, hindlimb stylopod muscle, triceps brachii
SYPL2	167	broad	yes	tibialis anterior, deltoid, gastrocnemius
HSP90AA1	313	ubiquitous	marker	endothelial cell, middle temporal gyrus, Brodmann (1909) area 23
PYGM	227	broad	marker	skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSP90AA1	13,713
PYGM	2,565
RYR1	2,177
CACNA1S	1,818
TRPC1	1,557
CACNG1	1,140
SLC8A3	1,057
SYPL2	707

Intra-cohort edges

A	B	Sources
CACNA1S	CACNG1	string_interaction
CACNA1S	RYR1	string_interaction
RYR1	SYPL2	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HSP90AA1	P07900	448
TRPC1	P48995	4
RYR1	P21817	2
CACNA1S	Q13698	2
PYGM	P11217	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SYPL2	Q5VXT5	81.24
SLC8A3	P57103	76.87
CACNG1	Q06432	76.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 78. Enrichment computed across 8 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ion homeostasis	3	102.0×	2e-04	RYR1, SLC8A3, TRPC1
vRNP Assembly	1	951.7×	0.011	HSP90AA1
Assembly and release of respiratory syncytial virus (RSV) virions	1	951.7×	0.011	HSP90AA1
Respiratory syncytial virus genome replication	1	951.7×	0.011	HSP90AA1
Drug-mediated inhibition of ERBB2 signaling	1	475.8×	0.011	HSP90AA1
Resistance of ERBB2 KD mutants to trastuzumab	1	475.8×	0.011	HSP90AA1
Resistance of ERBB2 KD mutants to sapitinib	1	475.8×	0.011	HSP90AA1
Resistance of ERBB2 KD mutants to tesevatinib	1	475.8×	0.011	HSP90AA1
Resistance of ERBB2 KD mutants to neratinib	1	475.8×	0.011	HSP90AA1
Resistance of ERBB2 KD mutants to osimertinib	1	475.8×	0.011	HSP90AA1
Resistance of ERBB2 KD mutants to afatinib	1	475.8×	0.011	HSP90AA1
Resistance of ERBB2 KD mutants to AEE788	1	475.8×	0.011	HSP90AA1
Resistance of ERBB2 KD mutants to lapatinib	1	475.8×	0.011	HSP90AA1
Drug resistance in ERBB2 TMD/JMD mutants	1	475.8×	0.011	HSP90AA1
Cardiac conduction	2	36.2×	0.011	RYR1, SLC8A3
Muscle contraction	2	25.7×	0.012	RYR1, SLC8A3
Scavenging by Class F Receptors	1	317.2×	0.014	HSP90AA1
Uptake and function of diphtheria toxin	1	317.2×	0.014	HSP90AA1
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	190.3×	0.021	HSP90AA1
Role of second messengers in netrin-1 signaling	1	173.0×	0.021	TRPC1
Sodium/Calcium exchangers	1	173.0×	0.021	SLC8A3
Reduction of cytosolic Ca++ levels	1	158.6×	0.021	SLC8A3
Constitutive Signaling by Overexpressed ERBB2	1	158.6×	0.021	HSP90AA1
eNOS activation	1	146.4×	0.022	HSP90AA1
Glycogen breakdown (glycogenolysis)	1	126.9×	0.024	PYGM
Platelet calcium homeostasis	1	119.0×	0.024	SLC8A3
Constitutive Signaling by EGFRvIII	1	119.0×	0.024	HSP90AA1
Sema3A PAK dependent Axon repulsion	1	112.0×	0.024	HSP90AA1
Signaling by ERBB2 ECD mutants	1	112.0×	0.024	HSP90AA1
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	95.2×	0.027	HSP90AA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
calcium ion transmembrane transport	4	105.3×	3e-06	SLC8A3, TRPC1, CACNA1S, CACNG1
positive regulation of muscle contraction	2	601.9×	2e-04	CACNA1S, CACNG1
cellular response to caffeine	2	383.0×	3e-04	RYR1, CACNA1S
calcium ion transport	3	68.0×	3e-04	RYR1, TRPC1, CACNA1S
striated muscle contraction	2	210.7×	6e-04	RYR1, CACNA1S
regulation of cardiac conduction	2	210.7×	6e-04	SLC8A3, TRPC1
skeletal muscle fiber development	2	135.9×	0.001	RYR1, CACNA1S
calcium ion import across plasma membrane	2	135.9×	0.001	SLC8A3, CACNA1S
regulation of cytosolic calcium ion concentration	2	95.8×	0.002	RYR1, TRPC1
release of sequestered calcium ion into cytosol	2	86.0×	0.002	RYR1, CACNA1S
skeletal muscle adaptation	1	2106.5×	0.004	CACNA1S
muscle contraction	2	52.0×	0.005	RYR1, CACNA1S
neurofibrillary tangle assembly	1	1053.2×	0.007	HSP90AA1
intracellular calcium ion homeostasis	2	36.3×	0.009	SLC8A3, SYPL2
positive regulation of protein polymerization	1	421.3×	0.012	HSP90AA1
protein unfolding	1	421.3×	0.012	HSP90AA1
sarcoplasmic reticulum calcium ion transport	1	421.3×	0.012	CACNG1
extraocular skeletal muscle development	1	351.1×	0.012	CACNA1S
regulation of skeletal muscle contraction	1	351.1×	0.012	SLC8A3
T-tubule organization	1	351.1×	0.012	SYPL2
chaperone-mediated autophagy	1	351.1×	0.012	HSP90AA1
telomerase holoenzyme complex assembly	1	351.1×	0.012	HSP90AA1
calcium ion export across plasma membrane	1	351.1×	0.012	SLC8A3
response to caffeine	1	300.9×	0.014	RYR1
positive regulation of cardiac muscle contraction	1	263.3×	0.014	HSP90AA1
modulation of excitatory postsynaptic potential	1	263.3×	0.014	SLC8A3
negative regulation of intracellular signal transduction	1	263.3×	0.014	SLC8A3
response to salt stress	1	234.1×	0.015	HSP90AA1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	210.7×	0.016	RYR1
regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	210.7×	0.016	CACNG1

Therapeutics

Drug target analysis

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

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
CACNA1S	BEPRIDIL
CACNG1	NIMODIPINE
HSP90AA1	TETRACYCLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1S	48	4
HSP90AA1	48	4
CACNG1	2	4
TRPC1	1	2
PYGM	1	3
RYR1	0	0
SLC8A3	0	0
SYPL2	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
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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HSP90AA1	1,350	Binding:1271, ADMET:55, Functional:22, Toxicity:2
CACNA1S	228	Binding:142, Functional:79, Toxicity:5, ADMET:2
TRPC1	19	Binding:15, ADMET:4
PYGM	18	Binding:18
RYR1	16	Binding:13, Functional:3
CACNG1	13	Binding:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HSP90AA1	3.6.4.10	non-chaperonin molecular chaperone ATPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1S	228
HSP90AA1	1,350

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; 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
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

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CACNA1S, CACNG1, HSP90AA1
B	Phased (≥1) drug, not yet approved	2	TRPC1, PYGM
C	Druggable family + PDB, no drug	1	RYR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SLC8A3, SYPL2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RYR1	16	—
SLC8A3	0	—
SYPL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.