CATH (https://www.cathdb.info) identifies domains in protein structures from wwPDB and classifies these into evolutionary superfamilies, thereby providing structural and functional annotations. There are two levels: CATH-B, a daily snapshot of the latest domain structures and superfamily assignments, and CATH+, with additional derived data, such as predicted sequence domains, and functionally coherent sequence subsets (Functional Families or FunFams). The latest CATH+ release, version 4.3, significantly increases coverage of structural and sequence data, with an addition of 65,351 fully-classified domains structures (+15%), providing 500 238 structural domains, and 151 million predicted sequence domains (+59%) assigned to 5481 superfamilies. The FunFam generation pipeline has been re-engineered to cope with the increased influx of data. Three times more sequences are captured in FunFams, with a concomitant increase in functional purity, information content and structural coverage. FunFam expansion increases the structural annotations provided for experimental GO terms (+59%). We also present CATH-FunVar web-pages displaying variations in protein sequences and their proximity to known or predicted functional sites. We present two case studies (1) putative cancer drivers and (2) SARS-CoV-2 proteins. Finally, we have improved links to and from CATH including SCOP, InterPro, Aquaria and 2DProt.

Central European Institute of Technology Masaryk University Brno 625 00 Czech Republic| National Centre for Biomolecular Research Faculty of Science Masaryk University Brno 602 00 Czech Republic

Department of Applied Physics Faculty of Science and Technology Universiti Kebangsaan Malaysia Bangi Selangor 43600 Malaysia

Department of Biological and Medical Sciences Faculty of Health and Life Sciences Oxford Brookes University Oxford OX3 0BP UK

Institute of Structural and Molecular Biology University College London London WC1E 6BT UK

National Centre for Biomolecular Research Faculty of Science Masaryk University Brno 602 00 Czech Republic

Regional Centre of Advanced Technologies and Materials Department of Physical Chemistry Faculty of Science Palacký University Olomouc Olomouc 771 46 Czech Republic

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