SIFT

What SIFT Is

SIFT (Sorting Intolerant From Tolerant) predicts whether an amino acid substitution affects protein function based on sequence homology. It aligns the protein sequence against related sequences from other species and evaluates whether the substitution occurs at a position that is conserved or variable across evolution. If the position is highly conserved and the substitution introduces an amino acid with different properties, SIFT predicts a deleterious effect.

Score Interpretation

SIFT scores range from 0 to 1. Unlike most pathogenicity predictors, lower scores indicate greater predicted damage.

Strengths and Limitations

SIFT is one of the oldest and most widely cited computational predictors in genetics, with a straightforward biological rationale: positions conserved across evolution are likely functionally important. It is applicable to any missense variant in any protein with sufficient homologous sequences.

However, SIFT is based on sequence conservation alone and does not consider protein three-dimensional structure, post-translational modifications, or protein-protein interactions. It may miss gain-of-function variants (where the new amino acid has an active harmful effect rather than a loss of the original function) and is less effective for positions with low sequence conservation across species.