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Despite the facile design\u00a0of DNA hybridization probes, their limited specificity poses challenges in clinical applications. Here, a differential reaction pathway probe (DRPP) based on a dynamic DNA reaction network is presented. DRPP leverages differences in reaction intermediate concentrations between SNV and WT groups, directing them into distinct reaction pathways. This generates a strong pulse\u2010like signal for SNV and a weak unidirectional increase signal for wild\u2010type (WT). Through the application of machine learning to fluorescence kinetic data analysis, the classification of SNV and WT signals is automated with an accuracy of 99.6%, significantly exceeding the 80.7% accuracy of conventional methods. Additionally, sensitivity for variant allele frequency (VAF) is enhanced down to 0.1%, representing a ten\u2010fold improvement over conventional\u00a0approaches. DRPP accurately identified\n                    <jats:italic>D614G<\/jats:italic>\n                    and\n                    <jats:italic>N501Y<\/jats:italic>\n                    SNVs in the\n                    <jats:italic>S<\/jats:italic>\n                    gene of SARS\u2010CoV\u20102 variants in patient swab samples with accuracy over 99% (n = 82). It determined the VAF of ovarian cancer\u2010related mutations\n                    <jats:italic>KRAS\u2010G12R<\/jats:italic>\n                    ,\n                    <jats:italic>NRAS\u2010G12C<\/jats:italic>\n                    , and\n                    <jats:italic>BRAF\u2010V600E<\/jats:italic>\n                    in both tissue and blood samples (n = 77), discriminating cancer patients and healthy individuals with significant difference (\n                    <jats:italic>p<\/jats:italic>\n                    &lt;\u00a00.001). The potential integration of DRPP into clinical diagnostics, along with rapid amplification techniques, holds promise for early disease diagnostics and personalized diagnostics.\n                  <\/jats:p>","DOI":"10.1002\/advs.202412680","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T13:34:42Z","timestamp":1738676082000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Reaction Pathway Differentiation Enabled Fingerprinting Signal for Single Nucleotide Variant Detection"],"prefix":"10.1002","volume":"12","author":[{"given":"Huixiao","family":"Yang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Organic\u2010Inorganic Composites Beijing Key Laboratory of Bioprocess Beijing Advanced Innovation Center for Soft Matter Science and Engineering College of Life Science and Technology Beijing University of Chemical Technology  Beijing 100029 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linghao","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organic\u2010Inorganic Composites Beijing Key Laboratory of Bioprocess Beijing Advanced Innovation Center for Soft Matter Science and Engineering College of Life Science and Technology Beijing University of Chemical Technology  Beijing 100029 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinmiao","family":"Kang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organic\u2010Inorganic Composites Beijing Key Laboratory of Bioprocess Beijing Advanced Innovation Center for Soft Matter Science and Engineering College of Life Science and Technology Beijing University of Chemical Technology  Beijing 100029 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunpei","family":"Si","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Zhangjiang Institute for Advanced Study and National Center for Translational Medicine Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Song","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Zhangjiang Institute for Advanced Study and National Center for Translational Medicine Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6629-9856","authenticated-orcid":false,"given":"Xin","family":"Su","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organic\u2010Inorganic Composites Beijing Key Laboratory of Bioprocess Beijing Advanced Innovation Center for Soft Matter Science and Engineering College of Life Science and Technology Beijing University of Chemical Technology  Beijing 100029 China"},{"name":"State Key Laboratory of Natural and Biomimetic Drugs 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