CACNA1C is known to be associated with arrhythmias and developmental disorders, while its role in epilepsy has remained unclear. In this study, we focused on CACNA1C mutations in focal epilepsy, one of the most common seizure types. Using trio-based whole-exome sequencing, we identified three de novo CACNA1C mutations in patients with focal epilepsy. Notably, we found that molecular sub-regional effects may help explain the phenotypic heterogeneity. These findings suggest that CACNA1C is potentially a candidate causative gene of focal epilepsy, warranting special attention due to its association with arrhythmias and the risk of sudden unexpected death in epilepsy (SUDEP). (https://jmg.bmj.com/content/early/2026/08/06/jmg-2025-110918)