Institute of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.
Department of Physiology and Biochemistry, McGill University, Montréal, QC, Canada.
Sci Data. 2024 May 14;11(1):495. doi: 10.1038/s41597-024-03327-8.
Single amino acid substitutions can profoundly affect protein folding, dynamics, and function. The ability to discern between benign and pathogenic substitutions is pivotal for therapeutic interventions and research directions. Given the limitations in experimental examination of these variants, AlphaMissense has emerged as a promising predictor of the pathogenicity of missense variants. Since heterogenous performance on different types of proteins can be expected, we assessed the efficacy of AlphaMissense across several protein groups (e.g. soluble, transmembrane, and mitochondrial proteins) and regions (e.g. intramembrane, membrane interacting, and high confidence AlphaFold segments) using ClinVar data for validation. Our comprehensive evaluation showed that AlphaMissense delivers outstanding performance, with MCC scores predominantly between 0.6 and 0.74. We observed low performance on disordered datasets and ClinVar data related to the CFTR ABC protein. However, a superior performance was shown when benchmarked against the high quality CFTR2 database. Our results with CFTR emphasizes AlphaMissense's potential in pinpointing functional hot spots, with its performance likely surpassing benchmarks calculated from ClinVar and ProteinGym datasets.
单个氨基酸的替换可以深刻影响蛋白质的折叠、动态和功能。区分良性和致病性替换的能力对于治疗干预和研究方向至关重要。鉴于对这些变体进行实验检查的局限性，AlphaMissense 已成为预测错义变体致病性的有前途的方法。由于不同类型的蛋白质可能表现出异质性，我们使用 ClinVar 数据评估了 AlphaMissense 在几个蛋白质组（例如可溶性、跨膜和线粒体蛋白质）和区域（例如跨膜、膜相互作用和高置信度 AlphaFold 片段）中的功效。我们的综合评估表明，AlphaMissense 具有出色的性能，MCC 评分主要在 0.6 到 0.74 之间。我们在无组织数据集和与 CFTR ABC 蛋白相关的 ClinVar 数据上观察到性能较低。然而，当与高质量的 CFTR2 数据库进行基准测试时，表现出优越的性能。我们对 CFTR 的结果强调了 AlphaMissense 识别功能热点的潜力，其性能可能超过从 ClinVar 和 ProteinGym 数据集计算得出的基准。
