biostudies-literatureLacoste JGovernment of OntarioNHGRI NIH HHSWyoming Affiliate of Susan G Komen Breast Cancer FoundationNational Institutes of HealthCancer Prevention and Research Institute of TexasNIGMS NIH HHSCanadian Institutes of Health Research6725-6741.e13https://www.ebi.ac.uk/biostudies/studies/S-EPMC11568917biostudies-literatureUnknown187(23)Widespread sequencing has yielded thousands of missense variants predicted or confirmed as disease causing. This creates a new bottleneck: determining the functional impact of each variant-typically a painstaking, customized process undertaken one or a few genes and variants at a time. Here, we established a high-throughput imaging platform to assay the impact of coding variation on protein localization, evaluating 3,448 missense variants of over 1,000 genes and phenotypes. We discovered that mislocalization is a common consequence of coding variation, affecting about one-sixth of all pathogenic missense variants, all cellular compartments, and recessive and dominant disorders alike. Mislocalization is primarily driven by effects on protein stability and membrane insertion rather than disrCellPervasive mislocalization of pathogenic coding variants underlying human disorders.PMC11568917UM1 HG011989RM1 HG010461R35 GM122547R35 GM137836R35 GM133658Senft RShafqat-Abbasi HRoth FPHaghighi MRyder PVYi SSReno CLacoste JHao TXiong XTaipale MSegal DCimini BANyirakanani CSingh SCalderwood MALin ZYMcClain GGCarpenter AETeelucksingh THill DEQian WWMiglietta EHaider SVidal MSahni NMurray RRPeng JGingras ACfalsePervasive mislocalization of pathogenic coding variants underlying human disorders.Widespread sequencing has yielded thousands of missense variants predicted or confirmed as disease causing. This creates a new bottleneck: determining the functional impact of each variant-typically a painstaking, customized process undertaken one or a few genes and variants at a time. Here, we established a high-throughput imaging platform to assay the impact of coding variation on protein localization, evaluating 3,448 missense variants of over 1,000 genes and phenotypes. We discovered that mislocalization is a common consequence of coding variation, affecting about one-sixth of all pathogenic missense variants, all cellular compartments, and recessive and dominant disorders alike. Mislocalization is primarily driven by effects on protein stability and membrane insertion rather than disr2024-01-01T00:00:00Z2024 Nov2026-06-06T13:56:49.208Z2026-05-31T03:10:10.93ZS-EPMC115689173935343810.1016/j.cell.2024.09.003