Pathogenic variations illuminate functional constraints in intrinsically disordered proteins

Intrinsically disordered regions (IDRs) play key roles in cellular signaling and regulation, yet their contribution to human disease remains poorly understood. Here, we analyzed nearly one million ClinVar missense variants, focusing on those located within IDRs defined by curated and predicted annotations. Pathogenic variants were significantly enriched in short linear motifs (SLiMs) and disordered binding regions, consistent with their central functional importance. To extend these insights beyond existing annotations, we applied <i>AlphaMissense</i> and uncovered localized "island-like" patterns of elevated pathogenicity within IDRs. Leveraging these signals, we developed a classifier to prioritize predicted ELM motifs (PEMs), revealing thousands of candidate functional sites linked to major disease classes, including neurological, cardiovascular, and cancer-associated genes. Case studies, including POLK and FOXP2, demonstrate how this approach connects genetic variation to molecular mechanisms. This framework provides a scalable strategy to interpret variants of uncertain significance and defines the functional constraints governing the disordered proteome.