Hypokalemic periodic paralysis, type 1

Summary

Hypokalemic periodic paralysis, type 1 (MONDO:0042979) is a disease caused by CACNA1S (GenCC Strong), with 5 cohort genes.

At a glance

• Causal gene: CACNA1S (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 2,538

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypokalemic periodic paralysis, type 1
Mondo ID	MONDO:0042979
OMIM	170400
UMLS	C3714580
MedGen	811387
GARD	0025854
Is cancer (heuristic)	no

Also known as: HOKPP1 · hypokalemic periodic paralysis, type 1

Data availability: 2,538 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn metal metabolism disorder › familial periodic paralysis › hypokalemic periodic paralysis › hypokalemic periodic paralysis, type 1

Related subtypes (1): hypokalemic periodic paralysis, type 2

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:

282 likely benign, 202 uncertain significance, 84 conflicting classifications of pathogenicity, 17 pathogenic, 5 likely pathogenic, 4 benign, 3 benign/likely benign, 3 pathogenic/likely pathogenic

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
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
1723138	NM_000083.3(CLCN1):c.2014C>G (p.Arg672Gly)	CLCN1	Pathogenic	no assertion criteria provided
143199	NM_000334.4(SCN4A):c.664C>T (p.Arg222Trp)	SCN4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143201	NM_000334.4(SCN4A):c.3404G>A (p.Arg1135His)	SCN4A	Pathogenic	criteria provided, multiple submitters, no conflicts
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
1708955	NM_000069.3(CACNA1S):c.182del (p.Ile61fs)	CACNA1S	Likely pathogenic	criteria provided, single submitter
1709679	NM_000069.3(CACNA1S):c.2293C>T (p.Gln765Ter)	CACNA1S	Likely pathogenic	criteria provided, single submitter
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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 13 · 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	hypokalemic periodic paralysis, type 1	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
SCN4A	Orphanet:681	Hypokalemic periodic paralysis
SCN4A	Orphanet:682	Hyperkalemic periodic paralysis
SCN4A	Orphanet:684	Paramyotonia congenita of Von Eulenburg
SCN4A	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
SCN4A	Orphanet:99734	Myotonia fluctuans
SCN4A	Orphanet:99735	Myotonia permanens
SCN4A	Orphanet:99736	Acetazolamide-responsive myotonia
CLCN1	Orphanet:614	Thomsen and Becker disease
SLC25A26	Orphanet:466784	Neonatal severe cardiopulmonary failure due to mitochondrial methylation defect

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

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
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	clinvar
CLCN1	HGNC:2019	ENSG00000188037	P35523	Chloride channel protein 1	clinvar
SLC25A26	HGNC:20661	ENSG00000144741	Q70HW3	Mitochondrial S-adenosylmethionine carrier protein	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.
SCN4A	Sodium channel protein type 4 subunit alpha	Pore-forming subunit of Nav1.4, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
CLCN1	Chloride channel protein 1	Voltage-gated chloride channel involved in skeletal muscle excitability.
SLC25A26	Mitochondrial S-adenosylmethionine carrier protein	Mitochondrial S-adenosyl-L-methionine/S-adenosyl-L-homocysteine antiporter.
ADIPOR1	Adiponectin receptor protein 1	Receptor for ADIPOQ, an essential hormone secreted by adipocytes that regulates glucose and lipid metabolism.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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	44.6×	0.002
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1S	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1ssu
SCN4A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a4su_mammal
CLCN1	Other/Unknown	no		ClC, Cl_channel-1, Cl-channel_core
SLC25A26	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf
ADIPOR1	Other/Unknown	no		AdipoR/HlyIII-related

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	3
triceps brachii	2
gastrocnemius	2
skeletal muscle tissue of rectus abdominis	2
gluteal muscle	1
apex of heart	1
muscle of leg	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
SCN4A	153	tissue_specific	yes	hindlimb stylopod muscle, gastrocnemius, skeletal muscle tissue of rectus abdominis
CLCN1	108	tissue_specific	marker	hindlimb stylopod muscle, triceps brachii, skeletal muscle tissue of rectus abdominis
SLC25A26	134	ubiquitous	marker	gastrocnemius, muscle of leg, apex of heart
ADIPOR1	286	ubiquitous	marker	blood, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1S	1,818
SCN4A	1,704
ADIPOR1	1,570
CLCN1	1,191
SLC25A26	705

Intra-cohort edges

A	B	Sources
CACNA1S	CLCN1	string_interaction
CLCN1	SCN4A	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCN1	P35523	9
SCN4A	P35499	3
ADIPOR1	Q96A54	3
CACNA1S	Q13698	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A26	Q70HW3	88.04

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 5 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
AMPK inhibits chREBP transcriptional activation activity	1	285.5×	0.026	ADIPOR1
SLC-mediated transport of organic cations	1	152.3×	0.026	SLC25A26
Axon guidance	2	18.1×	0.026	CACNA1S, SCN4A
Nervous system development	2	17.2×	0.026	CACNA1S, SCN4A
Interaction between L1 and Ankyrins	1	73.7×	0.038	SCN4A
Phase 0 - rapid depolarisation	1	69.2×	0.038	SCN4A
NCAM signaling for neurite out-growth	1	54.4×	0.040	CACNA1S
NCAM1 interactions	1	49.6×	0.040	CACNA1S
Stimuli-sensing channels	1	27.2×	0.055	CLCN1
R-HSA-425393	1	25.9×	0.055	SLC25A26
L1CAM interactions	1	24.0×	0.055	SCN4A
Developmental Biology	2	5.8×	0.055	CACNA1S, SCN4A
Cardiac conduction	1	21.8×	0.056	SCN4A
Muscle contraction	1	15.4×	0.072	SCN4A
SLC-mediated transmembrane transport	1	11.8×	0.087	SLC25A26
Transport of small molecules	1	5.0×	0.184	SLC25A26

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
muscle contraction	3	124.8×	4e-05	CACNA1S, SCN4A, CLCN1
S-adenosyl-L-methionine transport	1	3370.4×	0.002	SLC25A26
macromolecule methylation	1	3370.4×	0.002	SLC25A26
skeletal muscle adaptation	1	3370.4×	0.002	CACNA1S
regulation of skeletal muscle contraction by action potential	1	3370.4×	0.002	SCN4A
mitochondrial S-adenosyl-L-methionine transmembrane transport	1	3370.4×	0.002	SLC25A26
extraocular skeletal muscle development	1	561.7×	0.009	CACNA1S
leptin-mediated signaling pathway	1	481.5×	0.009	ADIPOR1
positive regulation of muscle contraction	1	481.5×	0.009	CACNA1S
adiponectin-activated signaling pathway	1	421.3×	0.010	ADIPOR1
cellular response to caffeine	1	306.4×	0.012	CACNA1S
neuronal action potential propagation	1	280.9×	0.012	CLCN1
negative regulation of epithelial cell migration	1	210.7×	0.014	ADIPOR1
fatty acid oxidation	1	210.7×	0.014	ADIPOR1
negative regulation of receptor signaling pathway via JAK-STAT	1	177.4×	0.014	ADIPOR1
striated muscle contraction	1	168.5×	0.014	CACNA1S
positive regulation of insulin receptor signaling pathway	1	168.5×	0.014	ADIPOR1
cardiac muscle cell action potential involved in contraction	1	140.4×	0.016	SCN4A
myoblast fusion	1	120.4×	0.017	CACNA1S
regulation of glucose metabolic process	1	112.3×	0.017	ADIPOR1
skeletal muscle fiber development	1	108.7×	0.017	CACNA1S
calcium ion import across plasma membrane	1	108.7×	0.017	CACNA1S
neuromuscular junction development	1	105.3×	0.017	CACNA1S
negative regulation of non-canonical NF-kappaB signal transduction	1	102.1×	0.017	ADIPOR1
chloride transport	1	91.1×	0.017	CLCN1
regulation of lipid metabolic process	1	86.4×	0.017	ADIPOR1
positive regulation of receptor signaling pathway via JAK-STAT	1	86.4×	0.017	ADIPOR1
endoplasmic reticulum organization	1	84.3×	0.017	CACNA1S
negative regulation of epithelial to mesenchymal transition	1	82.2×	0.017	ADIPOR1
hormone-mediated signaling pathway	1	80.2×	0.017	ADIPOR1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 3

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
SCN4A	CARBAMAZEPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1S	48	4
SCN4A	24	4
CLCN1	0	0
SLC25A26	0	0
ADIPOR1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1S
IMIPRAMINE	4	CACNA1S, SCN4A
HALOFANTRINE	4	CACNA1S
DROPERIDOL	4	CACNA1S
SAQUINAVIR	4	CACNA1S
DULOXETINE	4	CACNA1S
DIAZEPAM	4	CACNA1S
SERTINDOLE	4	CACNA1S, SCN4A
QUINIDINE	4	CACNA1S
LAMIVUDINE	4	CACNA1S
PIMOZIDE	4	CACNA1S, SCN4A
PHENYTOIN	4	CACNA1S, SCN4A
TERFENADINE	4	CACNA1S
CISAPRIDE	4	CACNA1S
SOLIFENACIN	4	CACNA1S
NIFEDIPINE	4	CACNA1S, SCN4A
DILTIAZEM	4	CACNA1S, SCN4A
NILOTINIB	4	CACNA1S
ASTEMIZOLE	4	CACNA1S
TERODILINE	4	CACNA1S
CLOZAPINE	4	CACNA1S
MIBEFRADIL	4	CACNA1S, SCN4A
DOFETILIDE	4	CACNA1S
THIORIDAZINE	4	CACNA1S
PAROXETINE	4	CACNA1S
DONEPEZIL	4	CACNA1S
IBUTILIDE	4	CACNA1S
SUNITINIB	4	CACNA1S
HALOPERIDOL	4	CACNA1S, SCN4A
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
SCN4A	95	Binding:69, Functional:18, ADMET:7, Toxicity:1
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: 5; 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, SCN4A
HALOFANTRINE	4	CACNA1S
DROPERIDOL	4	CACNA1S
SAQUINAVIR	4	CACNA1S
DULOXETINE	4	CACNA1S
DIAZEPAM	4	CACNA1S
SERTINDOLE	4	CACNA1S, SCN4A
QUINIDINE	4	CACNA1S
LAMIVUDINE	4	CACNA1S
PIMOZIDE	4	CACNA1S, SCN4A
PHENYTOIN	4	CACNA1S, SCN4A
TERFENADINE	4	CACNA1S
CISAPRIDE	4	CACNA1S
SOLIFENACIN	4	CACNA1S
NIFEDIPINE	4	CACNA1S, SCN4A
DILTIAZEM	4	CACNA1S, SCN4A
NILOTINIB	4	CACNA1S
ASTEMIZOLE	4	CACNA1S
TERODILINE	4	CACNA1S
CLOZAPINE	4	CACNA1S
MIBEFRADIL	4	CACNA1S, SCN4A
DOFETILIDE	4	CACNA1S
THIORIDAZINE	4	CACNA1S
PAROXETINE	4	CACNA1S
DONEPEZIL	4	CACNA1S
IBUTILIDE	4	CACNA1S
SUNITINIB	4	CACNA1S
HALOPERIDOL	4	CACNA1S, SCN4A
DASATINIB	4	CACNA1S

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CACNA1S, SCN4A
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	3	CLCN1, SLC25A26, ADIPOR1

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)
CLCN1	0	SCN4A
SLC25A26	0	—
ADIPOR1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.