Malignant hyperthermia, susceptibility to, 5

Summary

Malignant hyperthermia, susceptibility to, 5 (MONDO:0011163) is a disease caused by CACNA1S (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CACNA1S (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 3,074

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	malignant hyperthermia, susceptibility to, 5
Mondo ID	MONDO:0011163
MeSH	C535698
OMIM	601887
UMLS	C1866077
MedGen	356151
Is cancer (heuristic)	no

Also known as: CACNA1S malignant hyperthermia of anaesthesia · CACNA1S malignant hyperthermia of anesthesia · malignant hyperpyrexia susceptibility type 5 · malignant hyperthermia of anaesthesia caused by mutation in CACNA1S · malignant hyperthermia of anesthesia caused by mutation in CACNA1S · malignant hyperthermia susceptibility 5 · malignant hyperthermia susceptibility type 5 · malignant hyperthermia, susceptibility to, 5 · malignant hyperthermia, susceptibility to, type 5 · MHS5

Data availability: 3,074 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › malignant hyperthermia, susceptibility to › malignant hyperthermia, susceptibility to, 5

Related subtypes (5): malignant hyperthermia, susceptibility to, 1, malignant hyperthermia, susceptibility to, 2, malignant hyperthermia, susceptibility to, 3, malignant hyperthermia, susceptibility to, 4, 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:

286 likely benign, 195 uncertain significance, 90 conflicting classifications of pathogenicity, 17 pathogenic, 4 likely pathogenic, 3 benign, 2 benign/likely benign, 2 pathogenic/likely pathogenic, 1 drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069371	NM_000069.3(CACNA1S):c.436del (p.Gln146fs)	CACNA1S	Pathogenic	criteria provided, single submitter
1074196	NM_000069.3(CACNA1S):c.1274del (p.Cys425fs)	CACNA1S	Pathogenic	criteria provided, single submitter
1206372	NM_000069.3(CACNA1S):c.1246C>T (p.Gln416Ter)	CACNA1S	Pathogenic	criteria provided, single submitter
1356276	NM_000069.3(CACNA1S):c.78del (p.Arg26fs)	CACNA1S	Pathogenic	criteria provided, single submitter
1431806	NM_000069.3(CACNA1S):c.4173G>A (p.Trp1391Ter)	CACNA1S	Pathogenic	criteria provided, single submitter
1446481	NM_000069.3(CACNA1S):c.1087del (p.Leu363fs)	CACNA1S	Pathogenic	criteria provided, single submitter
1451963	NM_000069.3(CACNA1S):c.5229C>A (p.Cys1743Ter)	CACNA1S	Pathogenic	criteria provided, single submitter
1452647	NM_000069.3(CACNA1S):c.1234C>T (p.Arg412Ter)	CACNA1S	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452817	NM_000069.3(CACNA1S):c.4834del (p.Leu1612fs)	CACNA1S	Pathogenic	criteria provided, single submitter
1453569	NM_000069.3(CACNA1S):c.2324_2330del (p.Glu775fs)	CACNA1S	Pathogenic	criteria provided, single submitter
1454476	NC_000001.10:g.(?201012389)(201013604_?)del	CACNA1S	Pathogenic	criteria provided, single submitter
1455320	NM_000069.3(CACNA1S):c.1401_1414del (p.Asn468fs)	CACNA1S	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455433	NM_000069.3(CACNA1S):c.4210del (p.Ala1404fs)	CACNA1S	Pathogenic	criteria provided, single submitter
1459071	NM_000069.3(CACNA1S):c.85del (p.Arg29fs)	CACNA1S	Pathogenic	criteria provided, single submitter
1708506	NM_000069.3(CACNA1S):c.1252_1253del (p.Asn418fs)	CACNA1S	Pathogenic	criteria provided, single submitter
1723135	NM_000069.3(CACNA1S):c.2700G>C (p.Arg900Ser)	CACNA1S	Pathogenic	criteria provided, single submitter
17623	NM_000069.3(CACNA1S):c.3716G>A (p.Arg1239His)	CACNA1S	Pathogenic	criteria provided, multiple submitters, no conflicts
17624	NM_000069.3(CACNA1S):c.3715C>G (p.Arg1239Gly)	CACNA1S	Pathogenic	criteria provided, multiple submitters, no conflicts
1922123	NM_000069.3(CACNA1S):c.1366C>T (p.Gln456Ter)	CACNA1S	Pathogenic	criteria provided, single submitter
1066109	NM_000069.3(CACNA1S):c.4442-2A>G	CACNA1S	Likely pathogenic	criteria provided, single submitter
1502887	NM_000069.3(CACNA1S):c.1233-1G>A	CACNA1S	Likely pathogenic	criteria provided, multiple submitters, no conflicts
156288	NM_000069.3(CACNA1S):c.3256C>A (p.Arg1086Ser)	CACNA1S	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1697297	NM_000069.3(CACNA1S):c.3953+2C>G	CACNA1S	Likely pathogenic	criteria provided, single submitter
17626	NM_000069.3(CACNA1S):c.3257G>A (p.Arg1086His)	CACNA1S	drug response	reviewed by expert panel
1001609	NM_000069.3(CACNA1S):c.1466G>A (p.Arg489His)	CACNA1S	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009905	NM_000069.3(CACNA1S):c.2555C>T (p.Thr852Met)	CACNA1S	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1010689	NM_000069.3(CACNA1S):c.905A>G (p.Asn302Ser)	CACNA1S	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011195	NM_000069.3(CACNA1S):c.2245G>A (p.Glu749Lys)	CACNA1S	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011416	NM_000069.3(CACNA1S):c.3454A>G (p.Ile1152Val)	CACNA1S	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1018149	NM_000069.3(CACNA1S):c.5381G>A (p.Arg1794Gln)	CACNA1S	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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
CACNA1S	Strong	Autosomal dominant	malignant hyperthermia, susceptibility to, 5	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CACNA1S	HGNC:1397	ENSG00000081248	Q13698	Voltage-dependent L-type calcium channel subunit alpha-1S	gencc,clinvar
ADIPOR1	HGNC:24040	ENSG00000159346	Q96A54	Adiponectin receptor protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
ADIPOR1	Adiponectin receptor protein 1	Receptor for ADIPOQ, an essential hormone secreted by adipocytes that regulates glucose and lipid metabolism.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1S	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1ssu
ADIPOR1	Other/Unknown	no		AdipoR/HlyIII-related

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gluteal muscle	1
hindlimb stylopod muscle	1
triceps brachii	1
blood	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA1S	105	tissue_specific	marker	gluteal muscle, hindlimb stylopod muscle, triceps brachii
ADIPOR1	286	ubiquitous	marker	blood, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1S	1,818
ADIPOR1	1,570

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADIPOR1	Q96A54	3
CACNA1S	Q13698	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
AMPK inhibits chREBP transcriptional activation activity	1	713.8×	0.008	ADIPOR1
NCAM signaling for neurite out-growth	1	135.9×	0.016	CACNA1S
NCAM1 interactions	1	124.1×	0.016	CACNA1S
Axon guidance	1	22.6×	0.055	CACNA1S
Nervous system development	1	21.5×	0.055	CACNA1S
Developmental Biology	1	7.2×	0.134	CACNA1S

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skeletal muscle adaptation	1	8426.0×	0.004	CACNA1S
extraocular skeletal muscle development	1	1404.3×	0.006	CACNA1S
leptin-mediated signaling pathway	1	1203.7×	0.006	ADIPOR1
positive regulation of muscle contraction	1	1203.7×	0.006	CACNA1S
adiponectin-activated signaling pathway	1	1053.2×	0.006	ADIPOR1
cellular response to caffeine	1	766.0×	0.006	CACNA1S
negative regulation of epithelial cell migration	1	526.6×	0.006	ADIPOR1
fatty acid oxidation	1	526.6×	0.006	ADIPOR1
negative regulation of receptor signaling pathway via JAK-STAT	1	443.5×	0.006	ADIPOR1
striated muscle contraction	1	421.3×	0.006	CACNA1S
positive regulation of insulin receptor signaling pathway	1	421.3×	0.006	ADIPOR1
myoblast fusion	1	300.9×	0.007	CACNA1S
regulation of glucose metabolic process	1	280.9×	0.007	ADIPOR1
skeletal muscle fiber development	1	271.8×	0.007	CACNA1S
calcium ion import across plasma membrane	1	271.8×	0.007	CACNA1S
neuromuscular junction development	1	263.3×	0.007	CACNA1S
negative regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.007	ADIPOR1
regulation of lipid metabolic process	1	216.1×	0.007	ADIPOR1
positive regulation of receptor signaling pathway via JAK-STAT	1	216.1×	0.007	ADIPOR1
endoplasmic reticulum organization	1	210.7×	0.007	CACNA1S
negative regulation of epithelial to mesenchymal transition	1	205.5×	0.007	ADIPOR1
hormone-mediated signaling pathway	1	200.6×	0.007	ADIPOR1
release of sequestered calcium ion into cytosol	1	172.0×	0.008	CACNA1S
calcium ion transmembrane transport	1	105.3×	0.012	CACNA1S
muscle contraction	1	104.0×	0.012	CACNA1S
calcium ion transport	1	90.6×	0.013	CACNA1S
positive regulation of cold-induced thermogenesis	1	81.8×	0.014	ADIPOR1
negative regulation of cell growth	1	72.0×	0.015	ADIPOR1
glucose homeostasis	1	65.3×	0.016	ADIPOR1
skeletal system development	1	62.9×	0.016	CACNA1S

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1S	48	4
ADIPOR1	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): 0.

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

Symbol	Assays	Type breakdown
CACNA1S	228	Binding:142, Functional:79, Toxicity:5, ADMET:2
ADIPOR1	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1S	228

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
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)	1	CACNA1S
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ADIPOR1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ADIPOR1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.