PhyreRisk

PhyreRisk maps human genetic variants onto protein sequences and three-dimensional structures to enable interpretation of variant effects on protein function and interactions.

Key Features:

• Proteome content: Catalogues 20,214 canonical human proteins and 22,271 alternative protein sequences (isoforms).
• Structural coverage: Provides structural data for approximately 70% (14,035) of canonical proteins.
• Experimental structures: Integrates 18,874 experimental structures and 24,260 experimental structures of protein complexes.
• Pre-built models: Includes 84,818 pre-built models generated using the Phyre2 modelling tool.
• Protein interactions: Incorporates 55,732 experimentally validated protein–protein interactions from IntAct.
• Variant mapping: Supplies precomputed variant–structure mappings for known variants and supports mapping of novel user-specified variants onto protein sequences and structures.
• Input formats and coordinates: Accepts Ensembl, VCF, reference SNP ID (rsID), and HGVS notations and supports mapping using amino acid coordinates.
• Genome assemblies: Supports mapping against Human Build GRCh37 and GRCh38.
• Gene/protein search: Enables mapping and retrieval by specific gene or protein identifiers.

Scientific Applications:

• Variant functional interpretation: Interpreting the potential impact of single-nucleotide variants and other genetic changes on protein structure and function.
• Interaction impact analysis: Assessing how variants may affect protein–protein interactions by combining variant mappings with IntAct interactions and complex structures.
• Proteome-scale annotation: Providing structural annotation across the human proteome to support large-scale variant prioritization and analysis.
• Isoform-specific assessment: Evaluating variant consequences on alternative protein isoforms using the included isoform sequences.

Methodology:

Integrates 18,874 experimental structures and 84,818 Phyre2-generated models, incorporates 55,732 IntAct experimental interactions and 24,260 experimental complex structures, and maps variants provided in Ensembl, VCF, rsID, or HGVS formats onto protein sequences and structures for GRCh37 and GRCh38, including amino acid coordinate mapping.