Fold designability has been estimated by the number of families contained in that fold. Here, we show that among orthologous proteins, sequence divergence is higher for folds with greater numbers of families. Folds with greater numbers of families also tend to have families that appear more often in the proteome and greater promiscuity (the number of unique partner folds that the fold is found with within the same protein). We also find that many disease-related proteins have folds with relatively few families. In particular, a number of these proteins are associated with diseases occurring at high frequency. These results suggest that family counts reflect how certain structures are distributed in nature and is an important characteristic associated with many human diseases.