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Hydrophobic interactions have long been established as essential for stabilizing structured proteins as well as drivers of aggregation, but the impact of hydrophobicity on the functional significance of sequence variants has rarely been considered in a genomewide context. Here we test the role of hydrophobicity on functional impact across 70,000 disease- and non–disease-associated single-nucleotide polymorphisms (SNPs), using enrichment of disease association as an indicator of functionality. We find that functional impact is uncorrelated with hydrophobicity of the SNP itself and only weakly correlated with the average local hydrophobicity, but is strongly correlated with both the size and minimum hydrophobicity of the contiguously hydrophobic sequence (or “blob”) that contains the SNP. Disease association is found to vary by more than sixfold as a function of contiguous hydrophobicity parameters, suggesting utility as a prior for identifying causal variation. We further find signatures of differential selective constraint on hydrophobic blobs and that SNPs splitting a long hydrophobic blob or joining two short hydrophobic blobs are particularly likely to be disease associated. Trends are preserved for both aggregating and nonaggregating proteins, indicating that the role of contiguous hydrophobicity extends well beyond aggregation risk. [ABSTRACT FROM AUTHOR]