CACNA1S encodes the pore-forming alpha-1S subunit of the L-type voltage-gated calcium channel (dihydropyridine receptor, DHPR) in skeletal muscle 1. This channel mediates excitation-contraction coupling by directly coupling with the ryanodine receptor (RYR1) on the sarcoplasmic reticulum to trigger calcium release and muscle contraction 1. CACNA1S variants cause multiple neuromuscular disorders through distinct functional mechanisms. Gain-of-function mutations cause malignant hyperthermia (MH), a potentially fatal pharmacogenetic disorder characterized by hypermetabolic crisis during anesthesia exposure 2. Less than 1% of MH variants occur in CACNA1S, with RYR1 accounting for most cases 2. CACNA1S mutations also cause hypokalemic periodic paralysis through alterations in resting membrane potential 3. Novel loss-of-function mutations cause congenital myopathy presenting with perinatal hypotonia, weakness, and sarcoplasmic reticulum dilatation 1. These mutations demonstrate genotype-phenotype discordance, suggesting additional genetic modifiers in MH susceptibility 4. CACNA1S mutations represent an important but minority contributor to skeletal muscle channelopathies, with significant clinical implications for anesthetic management and muscle function.