PolyPhen-2 score¶
PolyPhen-2 estimates whether a missense variant may affect protein structure or function. It uses the changed amino acid, related protein sequences, and structural or annotation features when available. Scores near 0 are predicted to be more tolerated and scores near 1 are predicted to be more damaging. This is a prediction about protein function, not a diagnosis or a personal disease-risk estimate.
Score range in Gene Inspector Pro¶
PolyPhen-2 scores run from 0 to 1. The annotation source may also supply a category such as benign, possibly damaging, probably damaging, or unknown. Gene Inspector Pro preserves that supplied category when available.
PolyPhen-2 has more than one trained model, including HumDiv and HumVar. Their category cutoffs differ, so a numeric score should be interpreted with its supplied category and annotation version. A "damaging" category does not mean that the variant is clinically pathogenic.
When it applies¶
PolyPhen-2 is designed for coding missense variants. It does not assess non-coding, splice, truncating, structural, or most other variant types. It can return an unknown result when the protein alignment or other input is inadequate.
How to use it¶
Use PolyPhen-2 with population frequency, ClinVar submissions, the gene and disease mechanism, inheritance, genotype quality, and functional evidence. A low score does not prove a variant is harmless, and a high score does not prove that it causes disease.