Caveolin3 variants were associated with action potential prolongation. As Caveolin1 was recently identified in cardiomyocytes, we hypothesize that conserved isoform-specific protein interactions underlie human loss-of-function variants. To analyze the Caveolin1 and Caveolin3 interactome, we developed unbiased live-cell proteomic and isoform-specific mass spectrometry techniques. We demonstrate the functional relevance and pathogenic mechanism of a novel Caveolin3 interactor in gene-edited human iPSC-cardiomyocyte models.