PANTHER-PSEP is a new software tool for predicting non-synonymous genetic 
variants that may play a causal role in human disease. Several previous variant 
pathogenicity prediction methods have been proposed that quantify evolutionary 
conservation among homologous proteins from different organisms. PANTHER-PSEP 
employs a related but distinct metric based on 'evolutionary preservation': 
homologous proteins are used to reconstruct the likely sequences of ancestral 
proteins at nodes in a phylogenetic tree, and the history of each amino acid can 
be traced back in time from its current state to estimate how long that state 
has been preserved in its ancestors. Here, we describe the PSEP tool, and assess 
its performance on standard benchmarks for distinguishing disease-associated 
from neutral variation in humans. On these benchmarks, PSEP outperforms not only 
previous tools that utilize evolutionary conservation, but also several highly 
used tools that include multiple other sources of information as well. For 
predicting pathogenic human variants, the trace back of course starts with a 
human 'reference' protein sequence, but the PSEP tool can also be applied to 
predicting deleterious or pathogenic variants in reference proteins from any of 
the ∼100 other species in the PANTHER database.
AVAILABILITY AND IMPLEMENTATION: PANTHER-PSEP is freely available on the web at 
http://pantherdb.org/tools/csnpScoreForm.jsp Users can also download the 
command-line based tool at ftp://ftp.pantherdb.org/cSNP_analysis/PSEP/ CONTACT: 
pdthomas@usc.edu
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics 
online.