ProtVar is a flexible and user-friendly web-based resource for the contextualization and interpretation of human missense variation. It provides a comprehensive mapping between genomic, coding, protein, and structural positions, enabling researchers to quickly assess the functional and structural implications of variants. ProtVar pre-calculates all possible variants in the human proteome, allowing near-instantaneous mapping between data types. It integrates data and analyses from a wide range of resources to provide genomic, protein sequence, function, and structural annotations. The tool is accessible via a web server (https://www.ebi.ac.uk/protvar) and an API, allowing users to explore and download data, or programmatically access it. ProtVar supports various input formats, including genomic, cDNA, protein, and variant IDs, and automatically maps them to corresponding positions in the human genome and protein sequences. It also provides annotations for variant effects, including functional, population, and structural data, and offers predictions for protein stability, pockets, and interfaces. The tool is designed to be intuitive and accessible to a broad range of researchers, with a focus on ease of use and flexibility. ProtVar is freely available and open to all users without login requirements. The system is continuously updated and integrates with other resources to provide a comprehensive view of variant effects. It is intended to facilitate the interpretation of missense variation by providing a wide range of curated, evidence-based annotations and predictions. ProtVar is a valuable resource for researchers in the field of variant analysis, offering a flexible and comprehensive approach to understanding the functional and structural implications of human missense variants.ProtVar is a flexible and user-friendly web-based resource for the contextualization and interpretation of human missense variation. It provides a comprehensive mapping between genomic, coding, protein, and structural positions, enabling researchers to quickly assess the functional and structural implications of variants. ProtVar pre-calculates all possible variants in the human proteome, allowing near-instantaneous mapping between data types. It integrates data and analyses from a wide range of resources to provide genomic, protein sequence, function, and structural annotations. The tool is accessible via a web server (https://www.ebi.ac.uk/protvar) and an API, allowing users to explore and download data, or programmatically access it. ProtVar supports various input formats, including genomic, cDNA, protein, and variant IDs, and automatically maps them to corresponding positions in the human genome and protein sequences. It also provides annotations for variant effects, including functional, population, and structural data, and offers predictions for protein stability, pockets, and interfaces. The tool is designed to be intuitive and accessible to a broad range of researchers, with a focus on ease of use and flexibility. ProtVar is freely available and open to all users without login requirements. The system is continuously updated and integrates with other resources to provide a comprehensive view of variant effects. It is intended to facilitate the interpretation of missense variation by providing a wide range of curated, evidence-based annotations and predictions. ProtVar is a valuable resource for researchers in the field of variant analysis, offering a flexible and comprehensive approach to understanding the functional and structural implications of human missense variants.