In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss- or gain-of-function mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type , yet mutations when present are associated with worse prognosis. Employing a -driven ERMS tumor model and tp53 null (tp53) zebrafish, we define wild-type and patient-specific mutant effects on tumorigenesis. We demonstrate that is a major suppressor of tumorigenesis, where loss expands tumor initiation from <35% to >97% of animals. Characterizing three patient-specific alleles reveals that partially retains wild-type p53 apoptotic activity that can be exploited, whereas and encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. unexpectedly also predisposes to hedgehog-expressing medulloblastomas in the -driven ERMS-model.