to select templates that maximise sequence coverage and confidence. Constructs models for each selected template. Uses these models to provide pairwise distance constraints that are input to the ab initio and multi-template modelling tool Poing. Poing synthesises the user protein in the context of these distance constraints, modelled by springs. Regions for which there is no template information are modelled by the ab initio simplified physics model of Poing. The complete model generated by Poing is combined with the original templates as input to MODELLER. Applications Applications of Phyre and Phyre2 include protein structure prediction, function prediction, domain prediction, domain boundary prediction, evolutionary classification of proteins, guiding site-directed mutagenesis and solving protein crystal structures by molecular replacement. There are two linked resources that use Phyre predictions for the structure-based analysis of missense variants typically resulting from single-nucleotide polymorphisms. PhyreRisk is a database which maps genetic variants to experimental and Phyre-predicted protein structures. The protein page displays the experimental and predicted structures. Users can map variants from either genetic or protein coordinates. Missense3D is a tool which provides a stereochemical report on the effect of a missense variant on protein structure. Users can upload their own variants and coordinates, including both PDB structures and Phyre-predicted models. History Phyre and Phyre2 are the successors to the 3D-PSSM protein structure prediction system which has over 1400 citations to date. 3D-PSSM was designed and developed by Lawrence Kelley and Bob MacCallum in the Biomolecular modelling Lab at the Cancer Research UK. Phyre and Phyre2 were Lawrence Kelley in the Structural bioinformatics group, Imperial College London. Components of the Phyre and Phyre2 systems were developed by Benjamin Jefferys, Alex Herbert, and Riccardo Bennett-Lovsey. Research and development of both servers was supervised by Michael Sternberg. References Bioinformatics software Computational science