The analysis of sequence conservation patterns has been widely utilized to identify functionally important (catalytic and ligand-binding) protein residues for over a half-century. Despite decades of development, on average state-of-the-art non-template-based functional residue prediction methods must predict xe2x88xbc25% of a proteins total residues to correctly identify half of the proteins functional site residues. The overwhelming proportion of false positives results in reported F-Scores of xe2x88xbc0.3. We investigated the limits of current approaches, focusing on the so-far neglected impact of the specific choice of homologs included in multiple sequence alignments (MSAs).