{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:35:01Z","timestamp":1760060101609,"version":"build-2065373602"},"reference-count":58,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The TP53 gene, frequently mutated across multiple cancer types, plays a pivotal role in regulating the cell cycle and apoptosis through its protein, p53. Missense variants of uncertain significance (VUSs) in TP53 present challenges in understanding their impact on protein function and complicate clinical interpretation. This study aims to analyze the effects of missense VUSs in p53, as reported in the gnomAD database, with a specific focus on their impact on protein stability and phosphorylation. In this study, 33 missense VUSs in TP53 reported in the gnomAD database were analyzed using in silico tools, including PhosphositePlus v6.7.4, the Kinase Library v0.0.11, and Dynamut2. Of these analyzed variants, five disrupted known phosphorylation sites, while another five created new consensus sequences for phosphorylation. Moreover, 20 variants exhibited a moderate destabilizing effect on the protein structure. At least three missense VUSs were identified as potentially affecting p53 function, which may contribute to cancer development. These findings highlight the importance of integrating in silico structural and functional analysis to assess the pathogenic potential of missense VUSs.<\/jats:p>","DOI":"10.3390\/ijms26157455","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T15:56:16Z","timestamp":1754409376000},"page":"7455","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GnomAD Missense Variants of Uncertain Significance: Implications for p53 Stability and Phosphorylation"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9215-7191","authenticated-orcid":false,"given":"Fernando Daniel","family":"Garc\u00eda-Ayala","sequence":"first","affiliation":[{"name":"Instituto de Gen\u00e9tica Humana \u201cDr. Enrique Corona Rivera\u201d, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Programa de Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8875-5624","authenticated-orcid":false,"given":"Mar\u00eda de la Luz","family":"Ayala-Madrigal","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica Humana \u201cDr. Enrique Corona Rivera\u201d, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Programa de Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Peregrina-Sandoval","sequence":"additional","affiliation":[{"name":"Programa de Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Departamento de Biolog\u00eda Celular y Molecular, Centro Universitario de Ciencias Biol\u00f3gicas y Agropecuarias, Universidad de Guadalajara, Zapopan 44600, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7555-9851","authenticated-orcid":false,"given":"Jos\u00e9 Miguel","family":"Moreno-Ortiz","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica Humana \u201cDr. Enrique Corona Rivera\u201d, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Programa de Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8005-1304","authenticated-orcid":false,"given":"Anah\u00ed","family":"Gonz\u00e1lez-Mercado","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica Humana \u201cDr. Enrique Corona Rivera\u201d, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Programa de Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3848-8892","authenticated-orcid":false,"given":"Melva","family":"Guti\u00e9rrez-Angulo","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica Humana \u201cDr. Enrique Corona Rivera\u201d, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Programa de Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitl\u00e1n de Morelos 47600, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41563-022-01381-4","article-title":"A genomic mutational constraint map using variation in 76,156 human genomes","volume":"626","author":"Chen","year":"2023","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1093\/jlb\/lsx038","article-title":"The known unknown: The challenges of genetic variants of uncertain significance in clinical practice","volume":"4","year":"2017","journal-title":"J. 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