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Letter
Strengths and limitations of AlphaMissense in CPA1 missense variant classification
  1. Ya-Hui Wang1,2,
  2. Emmanuelle Masson3,4,
  3. Zhuan Liao1,2,
  4. Claude Férec3,
  5. Wen-Bin Zou1,2,
  6. Jian-Min Chen3
  1. 1 Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
  2. 2 Shanghai Institute of Pancreatic Diseases, Shanghai, China
  3. 3 Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200 Brest, France
  4. 4 CHRU Brest, Brest, France
  1. Correspondence to Dr Jian-Min Chen, Univ Brest, Inserm, EFS, UMR 1078, GGB, 22 avenue Camille Desmoulins, 29238 Brest, France; jian-min.chen{at}univ-brest.fr; Dr Wen-Bin Zou, Department of Gastroenterology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai 200433, People's Republic of China; dr.wenbinzou{at}hotmail.com

https://doi.org/10.1136/gutjnl-2024-332120

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    We read with interest the publication by Sándor and Sahin-Tóth, which classifies CPA1 missense variants based on functional data.1 Previous analyses of variants strongly associated with chronic pancreatitis (p.N256K, p.S282P and p.K374E) have demonstrated that pathogenic CPA1 variants result in proenzyme misfolding, leading to subsequent endoplasmic reticulum (ER) stress.2–6 In examining 50 CPA1 missense variants, Sándor and Sahin-Tóth revealed an inverse relationship between BiP mRNA expression, a marker of ER stress, in transfected HEK293T cells, and secretion levels. From these insights, they proposed a classification of CPA1 variants according to secretion levels: pathogenic (<10% of normal secretion), uncertain (10–20%) and benign (>20%).

    In silico prediction tools are pivotal for variant classification. AlphaMissense, a recent innovation, categorises missense variants across the human proteome into pathogenic, benign or ambiguous groups.7 Its predictions, primarily relying on structural context through an AlphaFold-based framework, substantially decrease dependence on human-curated data. AlphaMissense assigns pathogenicity scores ranging from 0 to 1, where higher scores suggest a greater likelihood of pathogenicity.

    In this study, we explored the capabilities of …

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    Footnotes

    • Contributors Y-HW collected variant and AlphaMissense data, conducted the analysis and revised the manuscript. EM collected variant and AlphaMissense data, reviewed the data and revised the manuscript. ZL and CF reviewed the data and revised the manuscript. W-BZ and J-MC conceived the study and drafted the manuscript. All authors approved the final manuscript.

    • Funding This work was supported by the National Natural Science Foundation of China (grant number 82222012 (W-BZ) and grant number 82120108006 (ZL)), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Association des Pancréatites Chroniques Héréditaires and the Association Gaétan Saleün, France.

    • Disclaimer The funding organisations did not have any involvement in the study design, data collection and analysis, or the preparation of this article. Furthermore, they were not involved in the decision to submit the article for publication.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.