VarSite

VarSite maps disease-associated and natural genetic variants onto three-dimensional protein structures, integrating variant data with structural data to assess impacts on protein structure and function.

Key Features:

• Database integration: Integrates variant data from UniProt and ClinVar and population variants from gnomAD with Protein Data Bank (PDB) structural entries.
• Variant mapping: Maps known disease-associated and natural variants onto human protein structures to contextualize amino acid changes within 3D coordinates.
• Structural annotations: Provides secondary structure assignments, and annotations of interactions with ligands, metals, DNA/RNA, and other proteins, plus metrics assessing potential functional impact.
• Visualization support: Employs 3dmol.js for structure inspection and provides compatibility with RasMol and PyMOL for exploring the spatial context of variants.
• Search by genomic coordinates: Enables lookup of specific variants by entering DNA coordinates of base changes.
• Agglomerative domain analyses: Maps disease and natural variants onto Pfam and CATH domains to analyze domain-specific variant distributions.
• Reporting: Generates comprehensive overviews for entire human proteins and detailed reports for individual variants.

Scientific Applications:

• Genetic research: Elucidating structural consequences of disease-associated mutations at the residue and domain level.
• Protein engineering: Assessing the structural context of amino acid substitutions to inform design of altered-function proteins.
• Drug discovery: Identifying variant-impacted sites and structural features relevant to ligand binding and therapeutic targeting.

Methodology:

Integrates UniProt, ClinVar, and gnomAD variant data with PDB structures and uses an image-based analytical approach to map variants onto structures and Pfam/CATH domains, producing protein-level overviews and variant-level reports.