In this study, we demonstrated that for arrhythmia‐associated CaM variants D131E and Q135P, reduced Ca2+ binding affinity, global alterations of Ca2+/CaM conformation, and changes to the interaction with the Cav1.2 channel are all significant factors which differentially contribute to the severe loss of CDI. The gene discussed is CACNA1C; the disease is cardiac arrhythmia.