This confirmed the trend previously observed of the ability of PCM models to interpolate in the protein feature space, especially for richer sets of proteins (more than 2000 data points) with an average Pearson's r of 0.325 compared to 0.311 for other proteins (Supplementary Table ). To decrease the sparsity of datasets, similarity-expanded common subsets were derived to focus on a subset of molecules and their analogues tested across a subset of variants. The latter drastically decreased the applicability domains of models (Supplementary Table )