Through adopting a multidisciplinary approach to better understand three LQTS‐associated CaM mutants (D95V, N97I and D131H), we reveal the molecular mechanisms which explain the perturbed structure–function relationships of these CaM variants, how their altered structures hinder complex formation with Kv7.1, and how this modulation results in a LQTS‐compatible IKs. The gene discussed is CALM2; the disease is familial long QT syndrome.