A multitude of cellular processes involve biomolecular condensates, which has led to the suggestion that diverse pathogenic mutations may dysregulate condensates. Although proof-of-concept studies have identified specific mutations that cause condensate dysregulation, the full scope of the pathological genetic variation that affects condensates is not yet known. Here, we comprehensively map pathogenic mutations to condensate-promoting protein features in putative condensate-forming proteins and find over 36,000 pathogenic mutations that plausibly contribute to condensate dysregulation in over 1,200 Mendelian diseases and 550 cancers. This resource captures mutations presently known to dysregulate condensates, and experimental tests confirm that additional pathological mutations do indeed affect condensate properties in cells. These findings suggest that condensate dysregulation may be a pervasive pathogenic mechanism underlying a broad spectrum of human diseases, provide a strategy to identify proteins and mutations involved in pathologically altered condensates, and serve as a foundation for mechanistic insights into disease and therapeutic hypotheses.

许多细胞过程都涉及生物分子凝聚物，这导致人们认为不同的致病突变可能会使凝聚物失调。尽管概念验证研究已经确定了导致冷凝物失调的特定突变，但影响冷凝物的病理性遗传变异的全部范围尚不清楚。在这里，我们全面地将致病突变映射到假定的凝结形成蛋白中的凝结促进蛋白特征，并发现了超过 36,000 个致病突变，这些突变可能导致 1,200 多种孟德尔疾病和 550 种癌症中的凝结失调。该资源捕获了目前已知的导致冷凝物失调的突变，实验测试证实额外的病理突变确实会影响细胞中的冷凝物特性。这些发现表明，冷凝物失调可能是广泛人类疾病的普遍致病机制，提供了识别与病理改变冷凝物相关的蛋白质和突变的策略，并作为深入了解疾病和治疗假设的机制的基础。