Genetic inactivation of SDHA can lead to succinate dehydrogenase (SDH)-deficiency and is implicated in a variety of human diseases. In particular, germline loss-of-function (LOF) mutations in SDHA increase the lifetime risk for developing a number of SDH-deficient cancers in heterozygous carriers. Currently, there are no highly effective medical therapies for unresectable or metastatic SDH-deficient cancer, but most are curable if resected at an early stage; therefore, early detection is critical. However, it has been difficult to determine which variants disrupt enzyme activity and actually confer cancer risk; over 700 SDHA missense variants have been reported in ClinVar, yet 97% are considered variants of uncertain significance (VUS) due to insufficient functional evidence. Carriers of SDHA VUS cannot be recommended enhanced clinical surveillance or genetic counseling, leaving those at risk unlikely to benefit from early detection. It is clear we are in great need of a model that enables the functional characterization of SDHA VUS, allowing us to identify which patients are truly at risk and should receive further screening.