{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T18:51:37Z","timestamp":1781808697258,"version":"3.54.5"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1014168","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000}}],"reference-count":22,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Missense variant interpretation often achieves useful predictive performance but remains mechanistically opaque, particularly in proteins that combine structured domains with intrinsically disordered regions (IDRs). We developed Gate &amp; Channel, a zero-parameter, first-principles framework for full-length TP53 missense variant analysis in which each prediction is generated by explicit IF-THEN gates derived from physicochemistry, geometry, structural constraints, and polymer physics rather than fitted weights. Variants are evaluated across independent channels representing distinct physical failure modes; a variant is predicted disruptive if any gate closes. A second hierarchical layer (\u201cGeta\u201d) encodes physically grounded post-closure exceptions, allowing sensitivity and specificity to be improved on disjoint variant populations.<\/jats:p>\n                  <jats:p>\n                    The v18 framework consists of 12 channels and 2 Getas spanning structured domains and IDRs, capturing DNA-contact disruption, Zn coordination, burial-dependent packing, secondary-structure compatibility, post-translational modification chemistry, short linear motif disruption (including a multi-partner coupled-folding face), proline-directed kinase recognition, and IDR-specific proline and glycine backbone constraints. Across 1,369 TP53 missense variants, the framework achieved\n                    <jats:bold>84.5% sensitivity and 89.1% positive predictive value<\/jats:bold>\n                    , with 90.9% sensitivity preserved in the DNA-binding core and all 9\/9 hotspot mutations captured. A post hoc audit of discordant IDR calls indicated that many apparent false positives had plausible molecular rationales, consistent with a distinction between molecular mechanism disruption and clinical penetrance.\n                  <\/jats:p>\n                  <jats:p>\n                    Applied to KRAS, TDP-43, and BRCA1, the same channels capture the dominant pathogenic mechanisms in each protein as a proof of principle, while residual missed variants name specific gates yet to be written. The framework is distributed as the open-source Python package\n                    <jats:monospace>pathogenicity-gates<\/jats:monospace>\n                    (v0.5.1, MIT). These results show that a substantial fraction of full-length TP53 missense variation can be resolved through explicit, auditable physical gates that carry meaning beyond TP53, with each remaining failure naming the next rule to be written.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014168","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T17:46:17Z","timestamp":1781199977000},"page":"e1014168","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A zero-parameter first-principles gate framework for full-length TP53 missense variant interpretation"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0755-403X","authenticated-orcid":true,"given":"Masamichi","family":"Iizumi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"issue":"6","key":"pcbi.1014168.ref001","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a000919","article-title":"The tumor suppressor p53: from structures to drug discovery","volume":"2","author":"AC Joerger","year":"2010","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"1","key":"pcbi.1014168.ref002","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/nrm3920","article-title":"Intrinsically disordered proteins in cellular signalling and regulation","volume":"16","author":"PE Wright","year":"2015","journal-title":"Nat Rev Mol Cell Biol"},{"key":"pcbi.1014168.ref003","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1146\/annurev-biochem-072711-164947","article-title":"Intrinsically disordered proteins and intrinsically disordered protein regions","volume":"83","author":"CJ Oldfield","year":"2014","journal-title":"Annu Rev Biochem"},{"issue":"13","key":"pcbi.1014168.ref004","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"PC Ng","year":"2003","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"pcbi.1014168.ref005","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"IA Adzhubei","year":"2010","journal-title":"Nat Methods"},{"issue":"6664","key":"pcbi.1014168.ref006","doi-asserted-by":"crossref","DOI":"10.1126\/science.adg7492","article-title":"Accurate proteome-wide missense variant effect prediction with AlphaMissense","volume":"381","author":"J Cheng","year":"2023","journal-title":"Science"},{"issue":"3","key":"pcbi.1014168.ref007","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"M Kircher","year":"2014","journal-title":"Nat Genet"},{"issue":"4","key":"pcbi.1014168.ref008","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants","volume":"99","author":"NM Ioannidis","year":"2016","journal-title":"Am J Hum Genet"},{"issue":"5289","key":"pcbi.1014168.ref009","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1126\/science.274.5289.948","article-title":"Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain","volume":"274","author":"PH Kussie","year":"1996","journal-title":"Science"},{"key":"pcbi.1014168.ref010","first-page":"1","article-title":"Phosphorylation site analysis in signal transduction","volume":"1002","author":"JJ Sims","year":"2013","journal-title":"Methods Mol Biol"},{"key":"pcbi.1014168.ref011","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: improving access to variant interpretations and supporting evidence","volume":"46","author":"MJ Landrum","year":"2018","journal-title":"Nucleic Acids Res"},{"issue":"5170","key":"pcbi.1014168.ref012","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1126\/science.8023157","article-title":"Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations","volume":"265","author":"Y Cho","year":"1994","journal-title":"Science"},{"key":"pcbi.1014168.ref013","unstructured":"Malecka KA, Ho WC, Bhakta SK, Olanich ME, Hubbard R, Cowan N, et al. 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