Calmodulin (CaM) is a ubiquitous calcium-sensing protein involved in the propagation of intracellular calcium signals and the regulation of events ranging from muscle contraction to cell excitability. The human genome contains three CaM genes (CALM 1-3) which encode for protein with identical primary sequences. Despite the redundancy of CaM, single missense mutations in even one of the six alleles are associated with disease phenotypes such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and early-onset severe long QT syndrome (esLQT). CPVT can lead to stress- and exercise-induced arrhythmias and sudden cardiac death; esLQT is characterized by a prolonged QT interval which can also result in ventricular fibrillation. Despite the devastating genetic disorders associated with CaM mutations, the molecular mechanisms by which these mutations manifest into dominant disease phenotypes have yet to be elucidated. Here, we present the crystal structures of several CaM disease mutants, one of which represents a novel CaM conformation not previously characterized. Significant structural changes are observed in both EF-hands III and IV of the C-lobe. In particular, the mutation disrupts the calcium coordination network in EF-hand III and results in abolished calcium binding, leading to CaM that resembles an intermediate between the Ca2+-CaM and apo-CaM states. In contrast, structures of other disease mutants revealed CaM conformations that closely resemble the wild type structure, with little positional shift in the EF-hand helices of either the N- or C-lobe. These structures can help explain the diverse effects of CaM mutations and the associated disease mechanisms, especially as CaM mutations have differential effects on the function of ryanodine receptor 2 and calcium-dependent inactivation of L-type calcium channels.