The penetrant D463H mutation in PRKCA, which encodes the kinase PKCα, is a biomarker and driver of chordoid glioma, a type of brain cancer. Here, we found that heterozygous knock-in expression of the D463H mutant in mice elicited the development of chondrosarcomas. The mutant protein kinase was catalytically inactive, but no such oncogenic phenotype was observed for the related inactivating mutation D463N, indicating that the lack of activity per se was not the cause of the oncogenicity of the D463H mutant. In cultured glioma cells, the behavior of the D463H mutant closely mirrored that of wild-type PKCα and retained ATP binding, unlike the related D463N mutant. Mechanistically, PKCα D463H displayed quantitative alterations in its interactome compared with that of the wild-type kinase, with enhanced association with epigenetic regulators. This change in the interactome aligned with transcriptomic changes that resembled an increased PKCα-induced expression program, with enhanced gene signatures mediated by BRD4, MYC, and TGF-β. D463H expression reduced the sensitivity of cells to the BET inhibitors JQ1 and AZD5153, indicating the functional importance of these pathways. The findings indicate that D463H is a dominant gain-of-function oncogenic mutant that operates through a noncatalytic allosteric mechanism.