Comprehensive annotation and analysis of human microproteins by human microprotein atlas platform

Small open reading frames (sORFs) and their encoded microproteins are increasingly recognized as a widespread but poorly characterized components of the human proteome. Here we show a Human Microprotein Atlas (HMPA) platform that integrates 617,462 human microproteins with sequence features, predicted three-dimensional structures, variant effect predictions, subcellular localization, essentiality, and bioactivity annotations. Structural analyses revealed substantial conformational diversity, and structure-based functional inference suggested roles in cellular regulation, signaling, and cell-cell communication. Deep learning-based analyses further prioritized microproteins with tissue-specific essentiality and enabled the prediction of diverse bioactivities across multiple functional categories. To support the exploration of these data, we also provide an interactive web server with sequence-, structure-, and function-oriented search and analysis utilities. This resource provides a systematic framework for studying microprotein biology and supports the discovery of functional and therapeutically relevant microproteins. Small open reading frames and their microproteins are largely unexplored despite their widespread translational activity in the human genome. Here, the authors introduce the human microprotein atlas (HMPA) platform, integrating structural and functional data to annotate the role of microproteins in cellular processes, improving our understanding of human microproteins.