Hyperkalemic periodic paralysis

Summary

Hyperkalemic periodic paralysis (MONDO:0008224) is a disease caused by SCN4A (GenCC Definitive), with 5 cohort genes and 3 clinical trials. Top therapeutic interventions include dichlorphenamide and lamotrigine.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: SCN4A (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 2,046
• Phenotypes (HPO): 29
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.5	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.17	United Kingdom	Validated
Point prevalence	<1 / 1 000 000	0.06	Netherlands	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0001315	Reduced tendon reflexes	Very frequent (80-99%)
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)
HP:0003457	EMG abnormality	Very frequent (80-99%)
HP:0003752	Episodic flaccid weakness	Very frequent (80-99%)
HP:0007215	Periodic hyperkalemic paralysis	Very frequent (80-99%)
HP:0100021	Cerebral palsy	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002153	Hyperkalemia	Frequent (30-79%)
HP:0002380	Fasciculations	Frequent (30-79%)
HP:0002486	Myotonia	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0000597	Ophthalmoparesis	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001522	Death in infancy	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0002047	Malignant hyperthermia	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002607	Bowel incontinence	Occasional (5-29%)
HP:0002900	Hypokalemia	Occasional (5-29%)
HP:0002902	Hyponatremia	Occasional (5-29%)
HP:0003198	Myopathy	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0003401	Paresthesia	Occasional (5-29%)
HP:0003712	Skeletal muscle hypertrophy	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0100613	Death in early adulthood	Occasional (5-29%)
HP:0100749	Chest pain	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperkalemic periodic paralysis
Mondo ID	MONDO:0008224
MeSH	D020513
OMIM	170500
Orphanet	682
DOID	DOID:14451
ICD-11	1308452752
NCIT	C123429
SNOMED CT	304737009
UMLS	C0238357
MedGen	68665
GARD	0000195
Is cancer (heuristic)	no

Also known as: adynamia episodica hereditaria · adynamia episodica hereditaria with or without myotonia · familial hyperkalemic periodic paralysis · familial hyperkalemic periodic paralysis (disorder) [ambiguous] · familial hyperPP · Gamstorp disease · Gamstorp episodic adynamy · hyperkalemic periodic paralysis · hyperkalemic periodic paralysis, type 2 · hyperkalemic PP · hyperKPP · hyperPP · HYPP · normokalemic periodic paralysis, potassium-sensitive · primary hyperkalemic periodic paralysis · primary hyperPP · sodium channel muscle disease

Data availability: 2,046 ClinVar variants · 4 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 › hyperkalemic periodic paralysis

Related subtypes (5): Andersen-Tawil syndrome, hypokalemic periodic paralysis, normokalemic periodic paralysis, periodic paralysis with later-onset distal motor neuropathy, thyrotoxic periodic paralysis

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:

296 uncertain significance, 231 likely benign, 28 conflicting classifications of pathogenicity, 20 benign, 17 pathogenic, 4 likely pathogenic, 3 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1723137	NM_000083.3(CLCN1):c.2015G>A (p.Arg672His)	CLCN1	Pathogenic	no assertion criteria provided
1061004	NM_000334.4(SCN4A):c.2143G>C (p.Ala715Pro)	GH-LCR	Pathogenic	criteria provided, single submitter
1363699	NM_000334.4(SCN4A):c.3263dup (p.Phe1089fs)	GH-LCR	Pathogenic	criteria provided, single submitter
1422620	NM_000334.4(SCN4A):c.2830_2831del (p.Phe944fs)	GH-LCR	Pathogenic	criteria provided, single submitter
1451612	NM_000334.4(SCN4A):c.4342C>G (p.Arg1448Gly)	GH-LCR	Pathogenic	criteria provided, single submitter
2044217	NM_000334.4(SCN4A):c.4472del (p.Leu1491fs)	GH-LCR	Pathogenic	criteria provided, single submitter
1074599	NM_000334.4(SCN4A):c.608T>A (p.Met203Lys)	SCN4A	Pathogenic	criteria provided, single submitter
1331173	NM_000334.4(SCN4A):c.665G>A (p.Arg222Gln)	SCN4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1352149	NM_000334.4(SCN4A):c.918G>A (p.Trp306Ter)	SCN4A	Pathogenic	criteria provided, single submitter
1362468	NM_000334.4(SCN4A):c.1775C>T (p.Thr592Ile)	SCN4A	Pathogenic	criteria provided, single submitter
1420693	NM_000334.4(SCN4A):c.1800C>G (p.Tyr600Ter)	SCN4A	Pathogenic	criteria provided, single submitter
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
1453704	NM_000334.4(SCN4A):c.584G>A (p.Trp195Ter)	SCN4A	Pathogenic	criteria provided, single submitter
1457445	NC_000017.10:g.(?62024385)(62034898_?)del	SCN4A	Pathogenic	criteria provided, single submitter
1458366	NM_000334.4(SCN4A):c.1249C>T (p.Arg417Ter)	SCN4A	Pathogenic	criteria provided, single submitter
1941601	NM_000334.4(SCN4A):c.1037-1G>A	SCN4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1980672	NM_000334.4(SCN4A):c.1925G>A (p.Trp642Ter)	SCN4A	Pathogenic	criteria provided, single submitter
2001963	NM_000334.4(SCN4A):c.1495del (p.Asp499fs)	SCN4A	Pathogenic	criteria provided, single submitter
2017990	NM_000334.4(SCN4A):c.1905C>A (p.Tyr635Ter)	SCN4A	Pathogenic	criteria provided, single submitter
1256465	NM_000334.4(SCN4A):c.4897C>G (p.Gln1633Glu)	GH-LCR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1918174	NM_000334.4(SCN4A):c.2078T>G (p.Ile693Ser)	GH-LCR	Likely pathogenic	criteria provided, single submitter
1475468	NM_000334.4(SCN4A):c.1762A>G (p.Ile588Val)	SCN4A	Likely pathogenic	criteria provided, single submitter
1487760	NM_000334.4(SCN4A):c.4098C>A (p.Asn1366Lys)	SCN4A	Likely pathogenic	criteria provided, single submitter
1034440	NM_000334.4(SCN4A):c.4827C>T (p.Ser1609=)	GH-LCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1039768	NM_000334.4(SCN4A):c.3394C>G (p.Arg1132Gly)	GH-LCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130233	NM_000334.4(SCN4A):c.3604G>A (p.Glu1202Lys)	GH-LCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1359989	NM_000334.4(SCN4A):c.2143G>A (p.Ala715Thr)	GH-LCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1418261	NM_000334.4(SCN4A):c.3696G>A (p.Leu1232=)	GH-LCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
143200	NM_000334.4(SCN4A):c.3386G>A (p.Arg1129Gln)	GH-LCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · 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
SCN4A	Definitive	Autosomal dominant	hyperkalemic periodic paralysis	24

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
CD79B	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
CLCN1	Orphanet:614	Thomsen and Becker disease
POLG2	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
RANBP2	Orphanet:178342	Inflammatory myofibroblastic tumor
RANBP2	Orphanet:263524	Acute necrotizing encephalopathy of childhood
RANBP2	Orphanet:88619	Familial acute necrotizing encephalopathy

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
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	gencc,clinvar
CD79B	HGNC:1699	ENSG00000007312	P40259	B-cell antigen receptor complex-associated protein beta chain	clinvar
CLCN1	HGNC:2019	ENSG00000188037	P35523	Chloride channel protein 1	clinvar
POLG2	HGNC:9180	ENSG00000256525	Q9UHN1	DNA polymerase subunit gamma-2	clinvar
RANBP2	HGNC:9848	ENSG00000153201	P49792	E3 SUMO-protein ligase RanBP2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
CD79B	B-cell antigen receptor complex-associated protein beta chain	Required in cooperation with CD79A for initiation of the signal transduction cascade activated by the B-cell antigen receptor complex (BCR) which leads to internalization of the complex, trafficking to late endosomes and antigen presentati…
CLCN1	Chloride channel protein 1	Voltage-gated chloride channel involved in skeletal muscle excitability.
POLG2	DNA polymerase subunit gamma-2	Accessory subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).
RANBP2	E3 SUMO-protein ligase RanBP2	E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.6

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	22.3×	0.220
Antibody/Immunoglobulin	1	5.8×	0.400
Enzyme (other)	1	2.4×	0.588
Transcription factor	1	1.6×	0.595
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN4A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a4su_mammal
CD79B	Antibody/Immunoglobulin	yes		Phos_immunorcpt_sig_ITAM, Ig_sub, Ig-like_dom
CLCN1	Other/Unknown	no		ClC, Cl_channel-1, Cl-channel_core
POLG2	Enzyme (other)	yes	2.7.7.7	Anticodon-bd, Gly-tRNA_synthase/POLG2, Anticodon-bd_dom_sf
RANBP2	Transcription factor	no		Ran_bind_dom, Znf_RanBP2, Cyclophilin-type_PPIase_dom

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	2
skeletal muscle tissue of rectus abdominis	2
gastrocnemius	1
granulocyte	1
lymph node	1
spleen	1
triceps brachii	1
left testis	1
oocyte	1
secondary oocyte	1
endothelial cell	1
mucosa of paranasal sinus	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN4A	153	tissue_specific	yes	hindlimb stylopod muscle, gastrocnemius, skeletal muscle tissue of rectus abdominis
CD79B	210	broad	marker	granulocyte, spleen, lymph node
CLCN1	108	tissue_specific	marker	hindlimb stylopod muscle, triceps brachii, skeletal muscle tissue of rectus abdominis
POLG2	249	ubiquitous	marker	secondary oocyte, oocyte, left testis
RANBP2	294	ubiquitous	marker	endothelial cell, sperm, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RANBP2	7,348
CD79B	2,382
SCN4A	1,704
POLG2	1,557
CLCN1	1,191

Intra-cohort edges

A	B	Sources
CLCN1	SCN4A	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG2	Q9UHN1	38
RANBP2	P49792	33
CLCN1	P35523	9
CD79B	P40259	5
SCN4A	P35499	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 58. 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
CD22 mediated BCR regulation	1	456.8×	0.046	CD79B
Strand-asynchronous mitochondrial DNA replication	1	228.4×	0.046	POLG2
IPs transport between nucleus and cytosol	1	76.1×	0.046	RANBP2
IP3 and IP4 transport between cytosol and nucleus	1	76.1×	0.046	RANBP2
IP6 and IP7 transport between cytosol and nucleus	1	76.1×	0.046	RANBP2
Interaction between L1 and Ankyrins	1	73.7×	0.046	SCN4A
Transport of Ribonucleoproteins into the Host Nucleus	1	71.4×	0.046	RANBP2
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	71.4×	0.046	RANBP2
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	71.4×	0.046	RANBP2
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	71.4×	0.046	CD79B
NEP/NS2 Interacts with the Cellular Export Machinery	1	69.2×	0.046	RANBP2
Phase 0 - rapid depolarisation	1	69.2×	0.046	SCN4A
Signaling by the B Cell Receptor (BCR)	1	69.2×	0.046	CD79B
Nuclear import of Rev protein	1	67.2×	0.046	RANBP2
Vpr-mediated nuclear import of PICs	1	67.2×	0.046	RANBP2
Transport of the SLBP independent Mature mRNA	1	65.3×	0.046	RANBP2
SUMOylation of SUMOylation proteins	1	65.3×	0.046	RANBP2
Transport of the SLBP Dependant Mature mRNA	1	63.4×	0.046	RANBP2
Rev-mediated nuclear export of HIV RNA	1	63.4×	0.046	RANBP2
Nuclear Pore Complex (NPC) Disassembly	1	61.7×	0.046	RANBP2
SUMOylation of ubiquitinylation proteins	1	58.6×	0.046	RANBP2
NS1 Mediated Effects on Host Pathways	1	57.1×	0.046	RANBP2
Transport of Mature mRNA Derived from an Intronless Transcript	1	54.4×	0.046	RANBP2
Viral Messenger RNA Synthesis	1	51.9×	0.046	RANBP2
SUMOylation of DNA replication proteins	1	49.6×	0.046	RANBP2
SUMOylation of RNA binding proteins	1	47.6×	0.046	RANBP2
snRNP Assembly	1	42.3×	0.050	RANBP2
Transcriptional activation of mitochondrial biogenesis	1	40.8×	0.050	POLG2
tRNA processing in the nucleus	1	39.4×	0.050	RANBP2
SUMOylation of chromatin organization proteins	1	31.7×	0.057	RANBP2

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
regulation of skeletal muscle contraction by action potential	1	3370.4×	0.004	SCN4A
muscle contraction	2	83.2×	0.004	SCN4A, CLCN1
positive regulation of DNA-directed DNA polymerase activity	1	421.3×	0.018	POLG2
mitochondrial DNA replication	1	306.4×	0.018	POLG2
nuclear export	1	306.4×	0.018	RANBP2
neuronal action potential propagation	1	280.9×	0.018	CLCN1
regulation of gluconeogenesis	1	224.7×	0.019	RANBP2
centrosome localization	1	177.4×	0.021	RANBP2
NLS-bearing protein import into nucleus	1	160.5×	0.021	RANBP2
cardiac muscle cell action potential involved in contraction	1	140.4×	0.021	SCN4A
intracellular glucose homeostasis	1	116.2×	0.022	RANBP2
DNA-templated DNA replication	1	112.3×	0.022	POLG2
response to amphetamine	1	99.1×	0.023	RANBP2
chloride transport	1	91.1×	0.023	CLCN1
B cell receptor signaling pathway	1	80.2×	0.024	CD79B
nucleocytoplasmic transport	1	78.4×	0.024	RANBP2
protein sumoylation	1	64.8×	0.027	RANBP2
sodium ion transport	1	54.4×	0.030	SCN4A
mRNA transport	1	52.7×	0.030	RANBP2
chloride transmembrane transport	1	47.5×	0.031	CLCN1
B cell differentiation	1	43.8×	0.032	CD79B
sodium ion transmembrane transport	1	40.6×	0.033	SCN4A
response to bacterium	1	38.7×	0.033	CD79B
mitochondrion organization	1	30.4×	0.041	POLG2
protein folding	1	20.7×	0.057	RANBP2
adaptive immune response	1	16.9×	0.067	CD79B
in utero embryonic development	1	14.4×	0.075	POLG2
immune response	1	9.4×	0.109	CD79B
negative regulation of transcription by RNA polymerase II	1	3.5×	0.261	RANBP2
signal transduction	1	3.2×	0.275	CD79B

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Dichlorphenamide	Phase 3 (in late-stage trials)

Drug target analysis

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

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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
SCN4A	CARBAMAZEPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN4A	24	4
CD79B	0	0
CLCN1	0	0
POLG2	0	0
RANBP2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CARBAMAZEPINE	4	SCN4A
PHENYTOIN	4	SCN4A
LAMOTRIGINE	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	SCN4A
SERTINDOLE	4	SCN4A
PIMOZIDE	4	SCN4A
NIFEDIPINE	4	SCN4A
DILTIAZEM	4	SCN4A
MIBEFRADIL	4	SCN4A
HALOPERIDOL	4	SCN4A
MEXILETINE	4	SCN4A
AMITRIPTYLINE	4	SCN4A
AMIODARONE	4	SCN4A
CHLORPROMAZINE	4	SCN4A
VIXOTRIGINE	3	SCN4A
ELECLAZINE	3	SCN4A
TETRODOTOXIN	3	SCN4A
TEDISAMIL	3	SCN4A
NITRENDIPINE	3	SCN4A
AJMALINE	3	SCN4A
PF-05089771	2	SCN4A
CIFENLINE	2	SCN4A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SCN4A	95	Binding:69, Functional:18, ADMET:7, Toxicity:1
CD79B	1	Binding:1
POLG2	1	Binding:1
RANBP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLG2	2.7.7.7	DNA-directed DNA polymerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

23 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)
CARBAMAZEPINE	4	SCN4A
PHENYTOIN	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	SCN4A
SERTINDOLE	4	SCN4A
PIMOZIDE	4	SCN4A
NIFEDIPINE	4	SCN4A
DILTIAZEM	4	SCN4A
MIBEFRADIL	4	SCN4A
HALOPERIDOL	4	SCN4A
MEXILETINE	4	SCN4A
AMITRIPTYLINE	4	SCN4A
AMIODARONE	4	SCN4A
CHLORPROMAZINE	4	SCN4A
VIXOTRIGINE	3	SCN4A
ELECLAZINE	3	SCN4A
TETRODOTOXIN	3	SCN4A
TEDISAMIL	3	SCN4A
NITRENDIPINE	3	SCN4A
AJMALINE	3	SCN4A
PF-05089771	2	SCN4A
CIFENLINE	2	SCN4A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN4A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	CD79B, POLG2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CLCN1, RANBP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CLCN1	0	SCN4A
CD79B	1	—
POLG2	1	—
RANBP2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	2
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00494507	PHASE3	COMPLETED	Hyper- and Hypokalemic Periodic Paralysis Study
NCT01939561	PHASE3	COMPLETED	Lamotrigine as Treatment of Myotonia
NCT07194174	Not specified	RECRUITING	Effect of Physical Training in Individuals With Hypokalemic and Hyperkalemic Periodic Paralysis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DICHLORPHENAMIDE	4	1
LAMOTRIGINE	4	1