CACNA1S

Chr 1ADAR

calcium voltage-gated channel subunit alpha1 S

Also known as: CACNL1A3, CCHL1A3, CMYO18, CMYP18, Cav1.1, DHPRM, HOKPP, HOKPP1

NCBI Gene: 779 ENSG00000081248 UniProt: Q13698 OMIM: 114208

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.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.524 OMIM phenotypes

Clinical Summary— CACNA1S

🧬

Gene-Disease Validity (ClinGen)

malignant hyperthermia, susceptibility to, 5 · ADModerate

Moderate evidence — consider for supplementary testing

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.000

Z-score 5.36

OE 0.39 (0.30–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.11Z-score

OE missense 1.01 (0.96–1.06)

1075 obs / 1064.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.39 (0.30–0.52)

0≤0.351.4

Missense OE?1.01 (0.96–1.06)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 36 / 91.3Missense obs/exp: 1075 / 1064.8Syn Z: -1.67

This gene — mechanism propensity

0.81top 10%

GOF

0.83top 10%

LOF

0.2190th %ile

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.

GOFprediction above median

DNprediction above median

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.