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Herein, we present a mechanistically guided Color\u2010Coding Strategy for Multiple Variants Based on Single\u2010Mutation\u2010Responsive Strand\u2010Displacement Padlock Probes that enables combinatorial color\u2010coded identification of genetic variants with minimal parallel reactions. By integrating multiple isothermal amplification reactions (\n                    <jats:italic>n<\/jats:italic>\n                    ) with multichannel strand displacement probes (m), the system establishes a theoretical\n                    <jats:italic>n<\/jats:italic>\n                    \u2010dimensional coding framework capable of resolving up to  variants in a single assay. Each variant is uniquely encoded by an \u201c\n                    <jats:italic>n<\/jats:italic>\n                    \u2010color codon\u201d and automatically decoded via a programmable algorithm. Using SARS\u2010CoV\u20102 as a model, we identified up to 15 variants using only three reaction tubes across RNA, synthetic DNA, pseudovirus, and clinical nasopharyngeal swabs (\n                    <jats:italic>n<\/jats:italic>\n                    = 76). In clinical evaluation, the assay achieved 100% positive agreement with RT\u2010qPCR for SARS\u2010CoV\u20102\u2010positive specimens and successfully assigned variant identities to 72 of 76 samples (94.7%). The platform achieves a reduced reaction number, experimental complexity, and cost compared to conventional approaches. Owing to its modular and programmable design, this strategy is readily adaptable to emerging variants, demonstrating its potential for pathogen surveillance, and genetic variant analysis.\n                  <\/jats:p>","DOI":"10.1002\/anie.9168476","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:23:32Z","timestamp":1785414212000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistically Guided Combinatorial Coding Based on Strand Displacement Probes for Multiplex Pathogen Variant Discrimination"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2672-1001","authenticated-orcid":false,"given":"Yidan","family":"Tang","sequence":"first","affiliation":[{"name":"Key Laboratory of Electroanalytical Chemistry Changchun Institute of Applied Chemistry Chinese Academy of Sciences  Changchun Jilin People's Republic of 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