Abstract
The assessment of functional effect of amino acid variants is a critical biological problem in proteomics for clinical medicine and protein engineering. Although natively occurring variants offer insights into deleterious variants, high-throughput deep mutational experiments enable comprehensive investigation of amino acid variants for a given protein. However, these mutational experiments are too expensive to dissect millions of variants on thousands of proteins. Thus, computational approaches have been proposed, but they heavily rely on hand-crafted evolutionary conservation, limiting their accuracy. Recent advancement in transformers provides a promising solution to precisely estimate the functional effects of protein variants on high-throughput experimental data. Here, we introduce a novel deep learning model, namely Rep2Mut-V2, which leverages learned representation from transformer models. Rep2Mut-V2 significantly enhances the prediction accuracy for 27 types of measurements of functional effects of protein variants. In the evaluation of 38 protein datasets with 118,933 single amino acid variants, Rep2Mut-V2 achieved an average Spearman's correlation coefficient of 0.7. This surpasses the performance of six state-of-the-art methods, including the recently released methods ESM, DeepSequence and EVE. Even with limited training data, Rep2Mut-V2 outperforms ESM and DeepSequence, showing its potential to extend high-throughput experimental analysis for more protein variants to reduce experimental cost. In conclusion, Rep2Mut-V2 provides accurate predictions of the functional effects of single amino acid variants of protein coding sequences. This tool can significantly aid in the interpretation of variants in human disease studies.