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Here, we present SKALE 2.0, a phase\u2010resolved geometric deep learning framework that represents proteins as multimodal structural graphs and learns mutation\u2010induced aggregation phenotypes directly from three\u2010dimensional topology. Across SOD1, TDP\u201043, MAPT, and PRNP, SKALE 2.0 recovered a conserved latent transition from nucleation to elongation while resolving distinct mutation\u2010specific phase sensitivities. Representative protein language model, AlphaFold\u2010derived feature, and non\u2010phase\u2010aware structural baselines failed to recover both phase\u2010dependent mutation modulation and phase separability, indicating that explicit phase conditioning is essential. The learned geometry showed that nucleation is preferentially coupled to buried hydrophobic perturbations, whereas elongation is shaped by solvent\u2010accessible interfaces that support fibril propagation. This framework explains how pathogenic variants can remain globally folded yet acquire aggregation competence through localized structural rewiring. Recombinant SOD1 experiments validated predicted suppressor, enhancer, and phase\u2010switch mutations, demonstrating that initiation and propagation can be tuned independently. SKALE 2.0 links atomic topology to phase\u2010specific assembly kinetics and enables a constraint\u2010aware design of aggregation suppressors.<\/jats:p>","DOI":"10.1002\/advs.76118","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T13:17:58Z","timestamp":1781702278000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Phase\u2010Resolved Geometric Deep Learning Framework Maps Structural Determinants of Disease\u2010Associated Protein Aggregation and Guides Suppressor Design"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4313-3072","authenticated-orcid":false,"given":"Jia Shen","family":"Sio","sequence":"first","affiliation":[{"name":"School of Science Monash University Malaysia Jalan Lagoon Selatan  Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1132-5669","authenticated-orcid":false,"given":"Wei Xuan Wilson","family":"Loo","sequence":"additional","affiliation":[{"name":"School of Science Monash University Malaysia Jalan Lagoon Selatan  Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9220-9685","authenticated-orcid":false,"given":"Yan Shan","family":"Loo","sequence":"additional","affiliation":[{"name":"School of Science Monash University Malaysia Jalan Lagoon Selatan  Selangor Malaysia"},{"name":"Department of Pharmaceutics and Biopharmaceutics University of Marburg Robert\u2010Koch\u2010Str. 4 Marburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen Xin","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Science Monash University Malaysia Jalan Lagoon Selatan  Selangor 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3169-5795","authenticated-orcid":false,"given":"Chen Seng","family":"Ng","sequence":"additional","affiliation":[{"name":"School of Science Monash University Malaysia Jalan Lagoon Selatan  Selangor 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