{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:53:55Z","timestamp":1790016835408,"version":"4.0.1"},"reference-count":77,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:00:00Z","timestamp":1771027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine at the Medical College of Wisconsin"},{"name":"Medical College of Wisconsin and the Intramural Research Program of the National Human Genome Research Institute"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genetic variation in ATP Binding Cassette Subfamily C Member 6 (ABCC6) can cause both pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI). There are 930 distinct missense variants in ABCC6 reported, 87% of which are of uncertain clinical significance (VUS). New approaches are needed to mechanistically interpret and classify these VUS. We developed 3D protein models of ABCC6 in three functionally relevant conformations to calculate the structural effects of variants. We also used three-dimensional (3D) hotspot detection and developed a mechanistic ontology for critical structure-based functions of ABCC6, enabling us to categorize genomic variants. We identified two 3D hotspots and six specific functions of ABCC6 which variants impact. From this, we propose a mechanism for pathogenicity for 41% of VUS according to their impacted function. We propose that 33 of these variants could be reclassified as Likely Pathogenic with the addition of these structure-based evidence. The mechanistic information we present will guide future research to better address calcification disorders and understand genetic variants. This work emphasizes the benefits of thorough, holistic, and protein-based approaches to genetic interpretation. Further, our VUS reclassification approach will improve the diagnosis of ABCC6-driven diseases, shortening diagnostic odysseys. We believe that computational structural genomics approaches will soon take prominence in genomics data interpretation and variant classification.<\/jats:p>","DOI":"10.3390\/ijms27041832","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T10:14:32Z","timestamp":1771236872000},"page":"1832","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multi-State Structural Genomics Enables Large-Scale, Mechanistic, and Context-Specific Classification of ABCC6 Genetic Variants Implicated in Calcification Diseases"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9378-4223","authenticated-orcid":false,"given":"Jessica B.","family":"Wagenknecht","sequence":"first","affiliation":[{"name":"Computational Structural Genomics Unit, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7494-6059","authenticated-orcid":false,"given":"Neshatul","family":"Haque","sequence":"additional","affiliation":[{"name":"Computational Structural Genomics Unit, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0716-2403","authenticated-orcid":false,"given":"Salomao D.","family":"Jorge","sequence":"additional","affiliation":[{"name":"Discovery and Innovation Laboratory, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Ratnasinghe","sequence":"additional","affiliation":[{"name":"Computational Structural Genomics Unit, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1640-6780","authenticated-orcid":false,"given":"Raul","family":"Urrutia","sequence":"additional","affiliation":[{"name":"Discovery and Innovation Laboratory, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Gahl","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shira G.","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7073-0525","authenticated-orcid":false,"given":"Michael T.","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Computational Structural Genomics Unit, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Data Science Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,14]]},"reference":[{"key":"ref_1","first-page":"235","article-title":"ATP-binding cassette (ABC) transporters in human metabolism and diseases","volume":"53","author":"Poledne","year":"2004","journal-title":"Physiol. Res."},{"key":"ref_2","unstructured":"O\u2019Neill, M.J.F. (2022, May 16). Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 610508. OMIM. 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