 This paper presents a novel approach to identifying functional sites in proteins. The authors use a combination of sequence conservation and biophysical models of stability to identify regions of the protein that are likely to be involved in protein-protein interactions or other functions. They then test these predictions experimentally and compare them to known functional sites. This approach has been validated on the example of missense mutations in the HPRT1 gene, which can lead to Leshenyhan syndrome. The results suggest that this approach could be useful for identifying potential drug targets and understanding the underlying causes of diseases caused by missense mutations. This article was authored by Mateo Cagliada, Sandro Botoro, Soran Lindemos, and others.