{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T21:22:57Z","timestamp":1783113777603,"version":"3.54.6"},"reference-count":30,"publisher":"Wiley","issue":"34","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82450113"],"award-info":[{"award-number":["82450113"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFA1306400"],"award-info":[{"award-number":["2024YFA1306400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Accurate prediction of variant functional impact is crucial for understanding human diseases, particularly for cancer\u2010related genes such as\n                    <jats:italic>TP53<\/jats:italic>\n                    . Advances in high\u2010throughput mutational assays have enhanced variant effect prediction (VEP), but missense classification remains challenging due to the limitations of broad, non\u2010gene\u2010specific models. Here we present CaVepP53, a\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010specific predictor fine\u2010tuned on perturbation\u2010based experimental variants. The model not only classifies mutations but also quantifies their pathogenicity by calculating Euclidean distances between the wild\u2010type and mutant embeddings and deriving confidence scores through logistic transformation. Benchmarking demonstrates that CaVepP53 significantly outperforms general\u2010purpose models, such as AlphaMissense (AM) and PrimateAI\u20103D, achieving higher accuracy, precision, and F1\u2010score in predicting pathogenic mutations. Competitive growth assay validation of 22 mutations further confirms CaVepP53's robustness, including 7 functional novel variants absent in the ClinVar database. Thus, by integrating protein language models with experimentally validated functional data, our approach enables accurate, interpretable VEP for\n                    <jats:italic>TP53<\/jats:italic>\n                    , overcoming limitations of predictors trained solely on evolutionary or clinical associations. We further extended this framework to five additional cancer\u2010related genes (\n                    <jats:italic>VHL, ATM, BRCA1, RAD51C<\/jats:italic>\n                    , and\n                    <jats:italic>BAP1<\/jats:italic>\n                    ), establishing a generalizable framework for gene\u2010specific VEP with potential applications in precision medicine.\n                  <\/jats:p>","DOI":"10.1002\/advs.202516332","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T19:26:46Z","timestamp":1775762806000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Causal Prediction of\n                    <i>TP53<\/i>\n                    Variant Pathogenicity Using a Perturbation\u2010Informed Protein Language Model"],"prefix":"10.1002","volume":"13","author":[{"given":"Huiying","family":"Chen","sequence":"first","affiliation":[{"name":"The Key Laboratory of Pancreatic Diseases of Zhejiang Province the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Pancreatic Diseases of Zhejiang Province the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boqiang","family":"Hu","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Pancreatic Diseases of Zhejiang Province the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuke","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Pancreatic Diseases of Zhejiang Province the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minfang","family":"Song","sequence":"additional","affiliation":[{"name":"Research Center for Life Sciences Computing Zhejiang Lab  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabeth Xinyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Science &amp; Medicine The Australian National University  Canberra Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyang","family":"Li","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Pancreatic Diseases of Zhejiang Province the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gefei","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Pancreatic Diseases of Zhejiang Province the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfen","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Pancreatic Diseases of Zhejiang Province the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Bone Marrow Transplantation Center the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinpeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Nebraska Food for Health Center Department of Food Science and Technology University of Nebraska  Lincoln Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Lin","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Pancreatic Diseases of Zhejiang Province the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbin","family":"Yin","sequence":"additional","affiliation":[{"name":"Nebraska Food for Health Center Department of Food Science and Technology University of Nebraska  Lincoln Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8934-1247","authenticated-orcid":false,"given":"Xingxu","family":"Huang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Pancreatic Diseases of Zhejiang Province the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Research Center for Life Sciences Computing Zhejiang Lab  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingbo","family":"Liang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Pancreatic Diseases of Zhejiang Province the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.07.035"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007510\u20100"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006045\u20100"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3404"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010024\u201001358\u20109"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae413"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz411"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102308\u20107"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439\u2010020\u201002199\u20103"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3027"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010021\u201001160\u20107"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010018\u20100461\u2010z"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010021\u201001201\u20101"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201004043\u20108"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010022\u201001618\u20102"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010023\u201001465\u20100"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2023.100687"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201019669\u2010x"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.04.009"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.ads0018"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010024\u201002039\u20104"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn8197"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092472"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010024\u201001800\u2010z"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.05.046"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.08.039"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010024\u201001799\u20103"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41421\u2010020\u20100165\u2010z"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1089\/crispr.2018.0014"}],"container-title":["Advanced 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