Mutations can alter degrons by abolishing motifs or adjacent key PTMs, which affects specific E3 ligase-substrate binding efficiency, and correspondingly cause rewiring of UPS signaling. Loss of-function mutations occurring in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. Thus, a comprehensive mutational landscape on degrome is urgent to illuminate their quantitative influence on degrons. We systematically investigated and quantified the impact of missense mutations on the functionality of a degron. As a result, 89,318 actionable mutations were identified that directly destroys UPS signaling. The remaining mutations would indirectly perturb E3-degron network. The functional outcomes were annotated into five types: altering degron motif, blocking phosphorylation signal, blocking ubiquitination signal, and substituting flanking lysine, rewiring degron network. A full list of degron regulatory network-rewiring mutations can be accessed here.