In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss- or gain-of-functionTP53mutations 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-typeTP53, yet mutations when present are associated with worse prognosis. Employing akRASG12D-driven ERMS tumor model and tp53 null (tp53-/-) zebrafish, we define wild-type and patient-specificTP53mutant effects on tumorigenesis. We demonstrate thattp53is a major suppressor of tumorigenesis, wheretp53loss expands tumor initiation from <35% to >97% of animals. Characterizing three patient-specific alleles reveals thatTP53C176Fpartially retains wild-type p53 apoptotic activity that can be exploited, whereasTP53P153ΔandTP53Y220Cencode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS.TP53P153Δunexpectedly also predisposes to hedgehog-expressing medulloblastomas in thekRASG12D-driven ERMS-model.