Medulloblastoma, the most common malignant pediatric brain tumor, arises from developmental aberrations of cerebellar precursor cells. The CUL3-RING ubiquitin ligase adaptor KBTBD4 is recurrently mutated in medulloblastoma subgroups 3 and 4. While KBTBD4 mutations confer a gain-of-function phenotype leading to aberrant degradation of transcriptional repressors, endogenous targets of this E3 ligase remain unknown. Here, we identify the PP2A-A scaffolding subunit of the PP2A phosphatase as a CRL3 KBTBD4 substrate. Using a combination of proteomics, cell biology, biochemical reconstitution, and cryo-EM structural analyses, we show that CRL3 KBTBD4 mediates orphan quality control by targeting free PP2A-A for degradation to safeguard phosphatase activity. Loss of KBTBD4 or its mutation in medulloblastoma cause PP2A-A accumulation, hence affecting phospho-dependent signaling pathways in cancer development. Disease mutations in KBTBD4 thus elicit a dual phenotype: gain-of-function degradation of transcriptional repressors combined with loss of PP2A quality control, which dysregulates multiple signaling events implicated in cancer, including telomere length regulation.