It is a worthy goal to completely characterize all human proteins in terms of 
their domains. Here, using the Pfam database, we asked how far we have 
progressed in this endeavour. Ninety per cent of proteins in the human proteome 
matched at least one of 5494 manually curated Pfam-A families. In contrast, 
human residue coverage by Pfam-A families was <45%, with 9418 automatically 
generated Pfam-B families adding a further 10%. Even after excluding predicted 
signal peptide regions and short regions (<50 consecutive residues) unlikely to 
harbour new families, for ∼38% of the human protein residues, there was no 
information in Pfam about conservation and evolutionary relationship with other 
protein regions. This uncovered portion of the human proteome was found to be 
distributed over almost 25 000 distinct protein regions. Comparison with 
proteins in the UniProtKB database suggested that the human regions that 
exhibited similarity to thousands of other sequences were often either divergent 
elements or N- or C-terminal extensions of existing families. Thirty-four per 
cent of regions, on the other hand, matched fewer than 100 sequences in 
UniProtKB. Most of these did not appear to share any relationship with existing 
Pfam-A families, suggesting that thousands of new families would need to be 
generated to cover them. Also, these latter regions were particularly rich in 
amino acid compositional bias such as the one associated with intrinsic 
disorder. This could represent a significant obstacle toward their inclusion 
into new Pfam families. Based on these observations, a major focus for 
increasing Pfam coverage of the human proteome will be to improve the definition 
of existing families. New families will also be built, prioritizing those that 
have been experimentally functionally characterized. Database URL: 
http://pfam.sanger.ac.uk/