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Reference: Brunham, L.R., Singaraja, R.R., Pape, T.D., Kejariwal, A., Thomas, P.D., Hayden, M.R. Accurate prediction of the functional significance of nucleotide polymorphisms and mutations in the ABCA1 gene. PLoS Genetics (2005) 1 (6) e83.
Hosted: Part of the Reference Genome Project undertaken by the Gene Ontology (GO) Consortium – the research community and databases involved in the application of GO. (http://www.pantherdb.org/tools/csnpScoreForm.jsp)

Summary:
PANTHER aligns a query sequence to hidden Markov models (HMMs) of protein families and subfamilies in its collection. The probability of a variant being pathogenic is calculated from the variation over each alignment column.

Methodology:
• The probability that a coding variant will affect protein function is estimated by a substitution position-specific evolutionary conservation (subPSEC) score.
• This score is a negative logarithm of the probability ratio of the wild-type and mutant amino acids at a certain position. It falls between 0 (neutral) and (approx.) -10 (most likely to be deleterious) and has been shown to correlate with degree of functional impairment.
• Also reported is Pdeleterious, a score that represents the probability of the variant having a deleterious effect on protein function. A subPSEC score of -3 corresponds to Pdeleterious of 0.5.

Input:
• The user submits a protein sequence (in FASTA format or just amino acid sequence) and a list of the substitutions to assess.
• A lot of the power of the algorithm comes from the HMM-generated alignments and therefore the user cannot upload alignments themselves.