Modifications of the amino acid sequence generally affect protein stability. Here, we use knowledge-based potentials to estimate the stability of protein structures under sequence variation. Calculations on a variety of protein scaffolds result in a clear distinction of known mutable regions from arbitrarily chosen control patches. For example, randomly changing the sequence of an antibody paratope yields a significantly lower number of destabilized mutants as compared to the randomization of comparable regions on the protein surface. The technique is computationally efficient and can be used to screen protein structures for regions that are amenable to molecular tinkering by preserving the stability of the mutated proteins.