-CDKN2A mutations lead to p16^INK4A loss while undermining CDK inhibition and cell cycle control.-CDKN2A mutations determine disrupted cell cycle checkpoints which are pivotal in glioma onset and advancement.-CDKN2A mutations underscore the importance of cell cycle governance in glioma prevention and malignancy.-CDKN2A mutation status could predict glioma outcomes and therapeutic responses. Here, CDKN2A is linked to central nervous system cancer.