SIFT Score Interpretation: Deleterious vs Tolerated

What the Score Represents

SIFT estimates whether a missense substitution is tolerated at its protein position. The model compares homologous sequences and treats substitutions at conserved positions as more likely to impair function.

The 0.05 Threshold

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.