Our genomic, computational, experimental, and clinical data indicate that a long right tail of activating non-E17K mutations in AKT1 and AKT2 induce aberrant PI3K signaling to varying degrees via distinct structural deformations of oncogenic AKT that dictate distinct pharmacologic sensitivities to AKT inhibitors of different mechanisms of action, thereby broadening the predictive biomarker of AKT inhibitor treatment in advanced cancers. The gene discussed is PIK3CA; the disease is cancer.