We have read with great interest the study by Wang et al 1 in which the authors evaluated the utility of the AlphaMissense prediction programme2 (https://alphamissense.hegelab.org) in the classification of missense CPA1 variants with respect to pathogenicity in chronic pancreatitis. While the AI-driven prediction performed relatively well, the authors highlighted potential shortcomings that can limit its value in clinical practice. Defining the pathogenic potential of CPA1 variants detected in pancreatitis cases can be challenging because the mechanistic basis of disease risk is unrelated to loss of CPA1 function and seems to be determined by mutation-induced misfolding and the ensuing endoplasmic reticulum (ER) stress.3–5 Recently, we used transiently transfected HEK 293T cells to measure the secretion efficiency and induction of BiP mRNA expression, a marker of ER stress, for 50 missense CPA1 variants from pancreatitis cases and healthy controls.6 We found that the best predictor of pathogenicity was loss of secretion (<10% of wild type) irrespective of BiP levels. This data set can serve as a reference for the assignment of clinical significance of novel CPA1 variants. In the present study, we set out to examine what fraction of novel CPA1 variants detected in real-world genetic testing can be classified as pathogenic and whether AlphaMissense can replace …

中文翻译：

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AlphaMissense 与胰腺炎病例中 13 种新型错义 CPA1 变异的实验室致病性预测


我们饶有兴趣地阅读了 Wang 等人的研究 1，其中作者评估了 AlphaMissense 预测程序 2 (https://alphamissense.hegelab.org) 在错义 CPA1 变异分类与慢性胰腺炎致病性方面的效用。虽然人工智能驱动的预测表现相对较好，但作者强调了可能限制其在临床实践中价值的潜在缺陷。定义胰腺炎病例中检测到的 CPA1 变异的致病潜力可能具有挑战性，因为疾病风险的机制基础与 CPA1 功能丧失无关，并且似乎是由突变诱导的错误折叠和随后的内质网 (ER) 应激决定的。 3– 5 最近，我们使用瞬时转染的 HEK 293T 细胞来测量来自胰腺炎病例和健康对照的 50 种错义 CPA1 变异体的分泌效率和 BiP mRNA 表达（ER 应激标志物）的诱导。6 我们发现致病性的最佳预测因子是分泌丧失（野生型的 <10%），与 BiP 水平无关。该数据集可以作为新 CPA1 变异临床意义分配的参考。在本研究中，我们着手研究在现实世界的基因测试中检测到的新型 CPA1 变体的哪一部分可以被归类为致病性，以及 AlphaMissense 是否可以取代……