AlphaGenome Atlas: in silico mutagenesis of the entire human genome improves prioritization and interpretation of non-coding variants

Deciphering the functional consequences of non-coding genetic variation remains a major challenge in genomics, limiting the interpretation and prioritization of variants with potential clinical or population-level significance.

To address this, the authors present AlphaGenome Atlas, a comprehensive resource for joint interpretation and prioritization of variant effects across the entire human genome. Using AlphaGenome, they predicted regulatory effects across thousands of molecular phenotypes for every possible human single nucleotide variant and many observed indels. These predictions were then used to derive a unified, interpretable AlphaGenome Variant Impact (AVI) score and to map cis-regulatory motifs across the genome.

AVI achieved state-of-the-art performance across diverse benchmarks, with improved prioritization of deleterious non-coding variants. Application of the combined Atlas resource helped solve an epileptic encephalopathy rare disease case, increased statistical power to detect rare non-coding variants driving population-level phenotypes, and enhanced mechanistic interpretation of these variants. The authors conclude that AlphaGenome Atlas improves prioritization and molecular interpretation of non-coding variants with genetic and clinical significance.