Benchmarking the AlphaGenome Variant Impact score against SpliceAI on post-release ClinVar classifications and experimental splicing assays

AlphaGenome's claimed gains over other genome-wide scores do not hold on ground truth excluded from its developers' analyses. On 87,666 post-release ClinVar rare single-nucleotide variants, AVI reached an intronic AUROC of 0.957, indistinguishable from SpliceAI (difference −0.005) and Pangolin (−0.006), and it trailed SpliceAI by 0.070 on deep intronic variants. It also ranked splice-altering variants below raw SpliceAI on six splicing assays and gave benign evidence to only 24% of benign variants, against 90% for SpliceAI.