Individuals who inherit a pathogenic mutation in SDHA have an increased risk of cancer. However, there is often insufficient evidence to properly assess pathogenicity, and the majority of variants identified are variants of uncertain significance (VUS). Incorporating functional evidence can enhance the clinical interpretation of SDHA VUS, but the functional criteria for SDHA-variant cancer pathogenicity are not well defined. In this work, I developed novel models for the functional characterization of SDHA variants. I then investigated what consequences distinguish cancer from non-cancer variants. These insights allow us to determine which SDHA VUS have cancer-like dysfunction, improving our ability to identify patients with increased cancer risk.