Normal cellular and physiological functions rely on functional proteins. Hence, proper folding of proteins into their native three-dimensional structures and the prevention of toxic misfolded protein accumulation are essential. Correct folding of a structured protein can be compromised by destabilizing amino acid substitutions that may arise due to missense mutations in the encoding gene. Accordingly, structurally destabilized proteins and protein misfolding play a key role in many hereditary diseases. To prevent the consequences of protein misfolding, cells have evolved protein quality control (PQC) mechanisms that rely on molecular chaperones to catalyze protein refolding or target misfolded proteins for degradation. In the present work, PQC-linked degradation was analyzed for two proteins, FLCN and Parkin, linked to the renal cancer predisposition disorder known as Birt-Hogg- Dubé syndrome and a monogenic form of Parkinson’s disease, respectively. In case of FLCN, most known single-site disease-linked variants appeared structurally destabilized and displayed a reduced abundance due to PQC-linked proteasomal degradation. In case of Parkin, systematic mapping of the protein abundance of >99% (9219 out of 9300) of all the possible single-site amino acid substitutions and nonsense variants revealed that destabilized variants are primarily located in structured regions while the disordered regions are more tolerant to mutations. Accordingly, the abundance data also correlated with phylogenetic conservation and with in silico prediction of the structural protein stability. Half of the known disease-linked Parkin missense variants were of low abundance, indicating that structural destabilization and degradation is a key molecular mechanism for the pathology.