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Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disabling disorder characterized by progressive ossification of skeletal muscle, fascia, tendons, and ligaments. These conditions manifest phenotypic overlap in the ossification of tendons and ligaments. We describe herein a patient with DISH, exhibiting heterotopic ossification of the posterior longitudinal ligament where clinical whole exome sequencing identified a variant within <jats:italic>ACVR1<\/jats:italic>, a gene implicated in FOP. This variant, p.K400E, is a novel variant, not identified previously, and occurs in a highly conserved region across orthologs. We used sequence\u2010based predicative algorithms, molecular modeling, and molecular dynamics simulations, to test the potential for p.K400E to alter the structure and dynamics of ACVR1. We applied the same modeling and simulation methods to established FOP variants, to identify the detailed effects that they have on the ACVR1 protein, as well as to act as positive controls against which the effects of p.K400E could be evaluated. Our in silico molecular analyses support p.K400E as altering the behavior of ACVR1. In addition, functional testing to measure the effect of this variant on BMP\u2010pSMAD 1\/5\/8 target genes was carried out which revealed this variant to cause increased <jats:italic>ID1<\/jats:italic> and <jats:italic>Msx2<\/jats:italic> expression compared with the wild\u2010type receptor. This analysis supports the potential for the variant of uncertain significance to contribute to the patient's phenotype.<\/jats:p>","DOI":"10.1002\/ajmg.a.61274","type":"journal-article","created":{"date-parts":[[2019,6,26]],"date-time":"2019-06-26T09:00:42Z","timestamp":1561539642000},"page":"1764-1777","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Molecular characterization of known and novel <i>ACVR1<\/i> variants in phenotypes of aberrant ossification"],"prefix":"10.1002","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3647-8148","authenticated-orcid":false,"given":"Aditi","family":"Gupta","sequence":"first","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael T.","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Research, Division 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