{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:16:32Z","timestamp":1788315392374,"version":"build-2803163510"},"reference-count":59,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Pathogenicity predictors exceed AUROC 0.97 on expert\u2010curated ClinVar, yet the monogenic\u2010epilepsy variant\u2010of\u2010uncertain\u2010significance backlog persists because pathogenicity alone provides no direction\u2010of\u2010effect, no scalable mechanism\u2010to\u2010treatment mapping, and no evidence that updates as ClinVar grows. SeizeVar couples a consensus pathogenicity head (random forest plus ESM\u20102 LoRA cross\u2010attention) to a gain\u2010versus\u2010loss\u2010of\u2010function mechanism classifier and a deterministic sodium\u2010channel mechanism\u2010direction rule. The framework was trained on a 49\u2010gene epilepsy panel (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20094576 labelled variants) and evaluated on six pairwise\u2010disjoint held\u2010out cohorts (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200911\u2009274) plus an external functional cohort with patch\u2010clamp\/TEVC labels (T2,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009415). SeizeVar's mechanism head reaches honest leave\u2010one\u2010gene\u2010out AUROC\u2009=\u20090.736 at 100% panel coverage and matches the proteome\u2010wide specialist LoGoFunc on fair full\u2010coverage comparison (0.770 vs. 0.760), whereas general\u2010purpose pathogenicity predictors are mechanism\u2010blind (AUROC \u2264\u20090.62). Applied to 29\u2009293 epilepsy VUS, the pipeline returned 4708 consensus Likely\u2010Pathogenic candidates, of which 1500 sodium\u2010channel variants received predicted mechanism\u2010direction labels (679 LoF\u2010leaning, 821 GoF\u2010leaning). By integrating pathogenicity, mechanism, and dynamic evidence on a shared probability scale, SeizeVar produces a mechanism\u2010annotated prioritisation list to support\u2014not replace\u2014expert variant curation; the outputs are computational predictions and a natural next step is prospective clinical validation. Reclassified\u2010VUS is released as a community benchmark for reclassification\u2010aware evaluation.\n                  <\/jats:p>","DOI":"10.1111\/cge.70206","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T17:08:20Z","timestamp":1782925700000},"page":"426-437","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Pathogenicity to Mechanism: A Variant Interpretation Framework for Monogenic Epilepsy"],"prefix":"10.1111","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3598-0469","authenticated-orcid":false,"given":"Shaopei","family":"Ye","sequence":"first","affiliation":[{"name":"Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1105-6638","authenticated-orcid":false,"given":"Peng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology The Second People's Hospital of Meishan  Meishan Sichuan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsr1406261"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23644"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.04.015"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17274"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac210"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.18113"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg509"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-021-00835-9"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010022\u201001120\u2010z"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade2574"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010023\u201001465\u20100"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.10.013"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010019\u20100690\u20102"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010021\u201000903\u2010z"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1153"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2023.11.005"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphg.93"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx054"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17747"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae125"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010023\u201001261\u20109"},{"key":"e_1_2_10_27_1","volume-title":"ACGS Best Practice Guidelines for Variant Classification in Rare Disease (v4.01)","author":"Ellard S.","year":"2020"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2104626"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/kxz041"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.01.017"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1151"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003819\u20102"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1052"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102308\u20107"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006045\u20100"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw865"},{"key":"e_1_2_10_38_1","doi-asserted-by":"crossref","unstructured":"C. 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