In this issue of the JCI, Yamaguchi et al. describe the effects of a somatic mosaic gain-of-function mutation (p.H1047R) in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic α subunit (p110α, encoded by PIK3CA) on the development of proliferative glomerulonephritis in a patient with PIK3CA-related overgrowth syndrome (PROS), providing evidence for the role of PI3K hyperactivation in proliferative podocytopathy and highlighting selective p110α inhibition as a potential rational therapy for the disease (Figure 1, B and C) (21). The gene discussed is PIK3CA; the disease is proliferative glomerulonephritis.