Hypokalemic periodic paralysis, type 2

Summary

Hypokalemic periodic paralysis, type 2 (MONDO:0013234) is a disease caused by SCN4A (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: SCN4A (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 615

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypokalemic periodic paralysis, type 2
Mondo ID	MONDO:0013234
MeSH	C567635
OMIM	613345
UMLS	C2750061
MedGen	413748
GARD	0015649
Is cancer (heuristic)	no

Also known as: HOKPP2 · hypokalemic periodic paralysis, type 2

Data availability: 615 ClinVar variants · 2 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 2

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

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:

326 uncertain significance, 127 conflicting classifications of pathogenicity, 41 likely benign, 36 benign, 31 benign/likely benign, 16 pathogenic, 11 likely pathogenic, 11 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
21155	NM_000334.4(SCN4A):c.3395G>A (p.Arg1132Gln)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
3582645	NM_000334.4(SCN4A):c.4665del (p.Asn1556fs)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
427072	NM_000334.4(SCN4A):c.4776G>A (p.Met1592Ile)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
543801	NM_000334.4(SCN4A):c.5104G>A (p.Glu1702Lys)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5896	NM_000334.4(SCN4A):c.2111C>T (p.Thr704Met)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5897	NM_000334.4(SCN4A):c.4774A>G (p.Met1592Val)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
5898	NM_000334.4(SCN4A):c.4342C>T (p.Arg1448Cys)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
5899	NM_000334.4(SCN4A):c.4343G>A (p.Arg1448His)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
5900	NM_000334.4(SCN4A):c.3466G>A (p.Ala1156Thr)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5903	NM_000334.4(SCN4A):c.3917G>T (p.Gly1306Val)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
5904	NM_000334.4(SCN4A):c.3938C>T (p.Thr1313Met)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
5905	NM_000334.4(SCN4A):c.4765G>A (p.Val1589Met)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
5908	NM_000334.4(SCN4A):c.3917G>C (p.Gly1306Ala)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5919	NM_000334.4(SCN4A):c.2024G>A (p.Arg675Gln)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
5920	NM_000334.4(SCN4A):c.3917G>A (p.Gly1306Glu)	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
633660	NM_000334.4(SCN4A):c.4379G>A (p.Arg1460Gln)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
21151	NM_000334.4(SCN4A):c.2014C>T (p.Arg672Cys)	SCN4A	Pathogenic	criteria provided, multiple submitters, no conflicts
5910	NM_000334.4(SCN4A):c.1333G>A (p.Val445Met)	SCN4A	Pathogenic	criteria provided, multiple submitters, no conflicts
5911	NM_000334.4(SCN4A):c.2006G>A (p.Arg669His)	SCN4A	Pathogenic	criteria provided, multiple submitters, no conflicts
5912	NM_000334.4(SCN4A):c.2015G>A (p.Arg672His)	SCN4A	Pathogenic	criteria provided, multiple submitters, no conflicts
5913	NM_000334.4(SCN4A):c.2014C>G (p.Arg672Gly)	SCN4A	Pathogenic	criteria provided, multiple submitters, no conflicts
5916	NM_000334.4(SCN4A):c.2014C>A (p.Arg672Ser)	SCN4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5917	NM_000334.4(SCN4A):c.3472C>T (p.Pro1158Ser)	SCN4A	Pathogenic	criteria provided, multiple submitters, no conflicts
591772	NM_000334.4(SCN4A):c.1173del (p.Phe392fs)	SCN4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
932430	NM_000334.4(SCN4A):c.4364T>C (p.Ile1455Thr)	SCN4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333663	NM_000334.4(SCN4A):c.4366G>T (p.Gly1456Trp)	GH-LCR	Likely pathogenic	criteria provided, single submitter
3582627	NM_000334.4(SCN4A):c.5431_5434dup (p.Pro1812fs)	GH-LCR	Likely pathogenic	criteria provided, single submitter
3582635	NM_000334.4(SCN4A):c.5061_5062insAGGTGACT (p.Leu1688delinsArgTer)	GH-LCR	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 10 · 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
RANBP2	Orphanet:178342	Inflammatory myofibroblastic tumor
RANBP2	Orphanet:263524	Acute necrotizing encephalopathy of childhood
RANBP2	Orphanet:88619	Familial acute necrotizing encephalopathy

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
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	gencc,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.
RANBP2	E3 SUMO-protein ligase RanBP2	E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN4A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a4su_mammal
RANBP2	Transcription factor	no		Ran_bind_dom, Znf_RanBP2, Cyclophilin-type_PPIase_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	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
RANBP2	294	ubiquitous	marker	endothelial cell, sperm, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RANBP2	7,348
SCN4A	1,704

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RANBP2	P49792	33
SCN4A	P35499	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. 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
IPs transport between nucleus and cytosol	1	190.3×	0.017	RANBP2
IP3 and IP4 transport between cytosol and nucleus	1	190.3×	0.017	RANBP2
IP6 and IP7 transport between cytosol and nucleus	1	190.3×	0.017	RANBP2
Interaction between L1 and Ankyrins	1	184.2×	0.017	SCN4A
Transport of Ribonucleoproteins into the Host Nucleus	1	178.4×	0.017	RANBP2
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	178.4×	0.017	RANBP2
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	178.4×	0.017	RANBP2
NEP/NS2 Interacts with the Cellular Export Machinery	1	173.0×	0.017	RANBP2
Phase 0 - rapid depolarisation	1	173.0×	0.017	SCN4A
Nuclear import of Rev protein	1	167.9×	0.017	RANBP2
Vpr-mediated nuclear import of PICs	1	167.9×	0.017	RANBP2
Transport of the SLBP independent Mature mRNA	1	163.1×	0.017	RANBP2
SUMOylation of SUMOylation proteins	1	163.1×	0.017	RANBP2
Transport of the SLBP Dependant Mature mRNA	1	158.6×	0.017	RANBP2
Rev-mediated nuclear export of HIV RNA	1	158.6×	0.017	RANBP2
Nuclear Pore Complex (NPC) Disassembly	1	154.3×	0.017	RANBP2
SUMOylation of ubiquitinylation proteins	1	146.4×	0.017	RANBP2
NS1 Mediated Effects on Host Pathways	1	142.8×	0.017	RANBP2
Transport of Mature mRNA Derived from an Intronless Transcript	1	135.9×	0.017	RANBP2
Viral Messenger RNA Synthesis	1	129.8×	0.017	RANBP2
SUMOylation of DNA replication proteins	1	124.1×	0.017	RANBP2
SUMOylation of RNA binding proteins	1	119.0×	0.017	RANBP2
snRNP Assembly	1	105.7×	0.018	RANBP2
tRNA processing in the nucleus	1	98.5×	0.019	RANBP2
SUMOylation of chromatin organization proteins	1	79.3×	0.021	RANBP2
Transport of Mature mRNA derived from an Intron-Containing Transcript	1	76.1×	0.021	RANBP2
ISG15 antiviral mechanism	1	75.1×	0.021	RANBP2
Signaling by ALK fusions and activated point mutants	1	75.1×	0.021	RANBP2
SUMOylation of DNA damage response and repair proteins	1	73.2×	0.021	RANBP2
Regulation of HSF1-mediated heat shock response	1	69.6×	0.021	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 2 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	8426.0×	0.002	SCN4A
nuclear export	1	766.0×	0.008	RANBP2
regulation of gluconeogenesis	1	561.7×	0.008	RANBP2
centrosome localization	1	443.5×	0.008	RANBP2
NLS-bearing protein import into nucleus	1	401.2×	0.008	RANBP2
cardiac muscle cell action potential involved in contraction	1	351.1×	0.008	SCN4A
intracellular glucose homeostasis	1	290.6×	0.008	RANBP2
response to amphetamine	1	247.8×	0.008	RANBP2
nucleocytoplasmic transport	1	195.9×	0.009	RANBP2
protein sumoylation	1	162.0×	0.010	RANBP2
sodium ion transport	1	135.9×	0.010	SCN4A
mRNA transport	1	131.7×	0.010	RANBP2
muscle contraction	1	104.0×	0.011	SCN4A
sodium ion transmembrane transport	1	101.5×	0.011	SCN4A
protein folding	1	51.7×	0.021	RANBP2
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	RANBP2

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
SCN4A	CARBAMAZEPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN4A	24	4
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): 0.

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

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

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

24 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
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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RANBP2

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)
RANBP2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.