2011) and thus lead to disease symptoms in the vast majority of carriers. On the other side of the spectrum, APA mutations such as V728I may manifest as primary aldosteronism without CNS symptoms in humans when present in the germline. This would explain the high number of carriers in the ExAC database. In the brain such rare CACNA1D variants inducing more subtle changes in Cav1.3 function may only be of disease relevance in a permissive genetic background. Here, ENPEP is linked to primary aldosteronism.