Spatial Distribution of Missense Variants within Complement Proteins Associates with Age Related Macular Degeneration.

We demonstrate for the first time that missense variants in complement genes cluster together spatially and are associated with AMD case/control status. Using this method, we can identify and variants of previously unknown significance that are predicted to destabilize the proteins. These variants, both in and outside spatial clusters, can predict tested protein expression changes, and we hypothesize the same is true for . identification of variants that impact gene expression allow for classification for previously classified as VUS. Further investigation is needed to validate the models for additional variants and to be applied to all AMD-associated genes.