Hypokalemic periodic paralysis: genes and variants

Genes linked to Hypokalemic periodic paralysis

• CACNA1S: Voltage-dependent L-type calcium channel subunit alpha-1S

  Its voltage sensing in skeletal-muscle transverse tubules mechanically activates RYR1 and couples membrane depolarization to sarcoplasmic-reticulum calcium release. Pathogenic variants can cause hypokalemic periodic paralysis, malignant-hyperthermia susceptibility, and congenital myopathy.

  14 disease-causing and 850 uncertain variants in CACNA1S are linked to Hypokalemic periodic paralysis.

• SCN4A: Sodium channel protein type 4 subunit alpha

  Its rapid sodium current initiates and propagates skeletal-muscle action potentials. Gain- and loss-of-function variants cause disorders of muscle excitability including sodium-channel myotonia, paramyotonia congenita, periodic paralysis, and some congenital myopathies.

  11 disease-causing and 134 uncertain variants in SCN4A are linked to Hypokalemic periodic paralysis.

• CLCN1: Chloride channel protein 1

  Its chloride conductance stabilizes the resting membrane potential of skeletal muscle and prevents repetitive firing after contraction. Loss-of-function variants cause myotonia congenita, with delayed muscle relaxation and stiffness.

  1 disease-causing and 0 uncertain variants in CLCN1 are linked to Hypokalemic periodic paralysis.

Where Hypokalemic periodic paralysis variants cluster

• SCN4A S4 of repeat II (positions 665–682): 4 of 11 disease-causing changes, 37.1× more than its size predicts.
• CACNA1S S4 of repeat III (positions 893–911): 4 of 14 disease-causing changes, 28.2× more than its size predicts.
• SCN4A S4 of repeat IV (positions 1446–1462): 3 of 11 disease-causing changes, 29.4× more than its size predicts.
• CACNA1S II (positions 418–664): 4 of 14 disease-causing changes, 2.2× more than its size predicts.

Known disease-causing variants in Hypokalemic periodic paralysis

Uncertain variants in Hypokalemic periodic paralysis that look disease-causing

Which prediction tools work for Hypokalemic periodic paralysis

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 87 out of 100
• SIFT: 86 out of 100
• phyloP: 81 out of 100
• PolyPhen-2: 77 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Hyperkalemic periodic paralysis is also caused by SCN4A variants; they fall mostly in different places as the Hypokalemic periodic paralysis variants (62 disease-causing).
• Paramyotonia congenita of Von Eulenburg is also caused by SCN4A variants; they fall mostly in different places as the Hypokalemic periodic paralysis variants (15 disease-causing).
• Potassium-aggravated myotonia is also caused by SCN4A variants; they fall partly in the same places as the Hypokalemic periodic paralysis variants (14 disease-causing).
• Congenital myopathy 22A, classic is also caused by SCN4A variants; they fall partly in the same places as the Hypokalemic periodic paralysis variants (8 disease-causing).
• Congenital myasthenic syndrome 17 is also caused by SCN4A variants; they fall mostly in different places as the Hypokalemic periodic paralysis variants (7 disease-causing).
• Congenital myotonia, autosomal dominant form is also caused by CLCN1 variants; they fall mostly in different places as the Hypokalemic periodic paralysis variants (92 disease-causing).
• Congenital myotonia, autosomal recessive form is also caused by CLCN1 variants; they fall mostly in different places as the Hypokalemic periodic paralysis variants (90 disease-causing).
• Skeletal muscle channelopathy is also caused by CLCN1 variants; they fall mostly in different places as the Hypokalemic periodic paralysis variants (11 disease-causing).

Diseases related to Hypokalemic periodic paralysis

• Skeletal muscle channelopathy, also linked to CACNA1S, CLCN1 and SCN4A
• Hyperkalemic periodic paralysis, also linked to CLCN1 and SCN4A
• Epilepsy, also linked to CACNA1S and SCN4A
• Amyotrophic lateral sclerosis, also linked to SCN4A
• Congenital myotonia, autosomal dominant form, also linked to CLCN1
• Congenital myotonia, autosomal recessive form, also linked to CLCN1
• Cardiac arrhythmia, also linked to SCN4A
• Sotos syndrome, also linked to SCN4A
• Congenital myasthenic syndrome 17, also linked to SCN4A
• Paramyotonia congenita of Von Eulenburg, also linked to SCN4A
• Potassium-aggravated myotonia, also linked to SCN4A
• Diabetes mellitus, also linked to CACNA1S

Frequently asked questions

Which genes are linked to Hypokalemic periodic paralysis?

In CATVariant, Hypokalemic periodic paralysis is linked to 3 analyzed proteins: CACNA1S (Voltage-dependent L-type calcium channel subunit alpha-1S), SCN4A (Sodium channel protein type 4 subunit alpha) and CLCN1 (Chloride channel protein 1).

How many genetic variants are linked to Hypokalemic periodic paralysis?

1,083 variants: 26 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 984 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hypokalemic periodic paralysis look disease-causing?

8 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CACNA1S R1239C, CACNA1S R897S, CACNA1S R1086G, CACNA1S M578V and CACNA1S R1086C. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Hypokalemic periodic paralysis?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.87, based on 12 disease-causing and 98 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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