Lead is a highly toxic metal that severely perturbs physiological processes even at sub-micromolar levels, often by disrupting the Ca signaling pathways. Recently, Pb-associated cardiac toxicity has emerged, with potential involvement of both the ubiquitous Ca sensor protein calmodulin (CaM) and ryanodine receptors. In this work, we explored the hypothesis that Pb contributes to the pathological phenotype of CaM variants associated with congenital arrhythmias. We performed a thorough spectroscopic and computational characterization of CaM conformational switches in the co-presence of Pb and four missense mutations associated with congenital arrhythmias, namely N53I, N97S, E104A and F141L, and analyzed their effects on the recognition of a target peptide of RyR2. When bound to any of the CaM variants, Pb is difficult to displace even under equimolar Ca concentrations, thus locking all CaM variants in a specific conformation, which exhibits characteristics of coiled-coil assemblies. All arrhythmia-associated variants appear to be more susceptible to Pb than wild type (WT) CaM, as the conformational transition towards the coiled-coil conformation occurs at lower Pb, regardless of the presence of Ca, with altered cooperativity. The presence of arrhythmia-associated mutations specifically alters the cation coordination of CaM variants, in some cases involving allosteric communication between the EF-hands in the two domains. Finally, while WT CaM increases the affinity for the RyR2 target in the presence of Pb, no specific pattern could be detected for all other variants, ruling out a synergistic effect of Pb and mutations in the recognition process.