ESMRank: learning-to-rank prediction of missense variant effects from deep mutational scanning data

Predicting the functional effects of missense variants is limited both by predictor performance and by the lack of principled strategies to integrate heterogeneous multiplexed assays of variant effect (MAVEs), including deep mutational scanning, into transferable sequence-function models. Here, we show that redundancy among partially overlapping deep mutational scanning experiments, often treated as noise, yields a consensus landscape of mutational constraint. We introduce "variant soundness", an overlap-aware rank-fusion score that uses cross-experiment consistency to derive an assay-agnostic ordering of mutational tolerance within proteins. Applied to ~1100 MAVEs spanning over two million missense variants, this approach reveals a mutational landscape enriched for structural stability constraints. Guided by this integrated signal, we develop ESMRank, a sequence-based learning-to-rank predictor combining ESM2 representations with physicochemical descriptors. Under strict protein-level partitioning, ESMRank outperforms widely used predictors across abundance-, folding-, and stability-related assays in ProteinGym and Domainome. Predicted deleterious variants are enriched for ClinVar pathogenicity and, in CFTR, correlate with folding efficiency, channel activity, and pharmacological responsiveness. Together, these results turn assay redundancy into a scalable resource for interpretable missense variant prediction.