CACNA1S
Chr 1ADARcalcium voltage-gated channel subunit alpha1 S
Also known as: CACNL1A3, CCHL1A3, CMYO18, CMYP18, Cav1.1, DHPRM, HOKPP, HOKPP1
The protein forms the pore-forming alpha-1S subunit of L-type voltage-gated calcium channels in skeletal muscle and plays a critical role in excitation-contraction coupling by interacting with RYR1 to trigger calcium release from the sarcoplasmic reticulum. Mutations cause hypokalemic periodic paralysis, thyrotoxic periodic paralysis, and malignant hyperthermia susceptibility, following an autosomal dominant inheritance pattern. The gene is extremely intolerant to loss-of-function variants (pLI near 1.0), indicating that such mutations are likely highly deleterious.
Moderate evidence — consider for supplementary testing
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
200 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 2 | 0 | 0 | 0 | 2 |
Likely Pathogenic | 2 | 0 | 0 | 0 | 2 |
VUS | 5 | 100 | 13 | 1 | 119 |
Likely Benign | 0 | 2 | 21 | 46 | 69 |
Benign | 0 | 1 | 0 | 0 | 1 |
Conflicting | — | 7 | |||
| Total | 9 | 103 | 34 | 47 | 200 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
CACNA1S · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools