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Pathogenic variants affecting alpha-2 smooth muscle actin () account for approximately 20% of nonsyndromic familial thoracic aortic aneurysms (TAA) and confer a high risk of dissection; however, the cell type-specific transcriptional mechanisms underlying -associated TAA remain poorly defined, particularly for variants of uncertain significance. In this study, we investigated the transcriptional and cellular effects of a novel p.Met49Thr mutation identified in a young male in his early twenties who developed a dissected ascending aortic aneurysm without traditional risk factors. Using clinically archived formalin-fixed paraffin-embedded (FFPE) aortic tissue, we isolated intact nuclei and performed single-nucleus RNA sequencing (snRNA-Seq) to generate 17,938 transcriptomes. Relative to a non-genetic hypertensive TAA control, -p.Met49Thr aortic tissue displayed marked expansion of vascular smooth muscle cells (VSMCs) (70.6% vs. 39.7%), accompanied by upregulation of proliferation-associated transcripts including , , , and . Lineage tracing via trajectory analysis revealed transcriptional progression from quiescent to pro-proliferative VSMC states enriching for human loci associated with aortic strain and diameter. Histological evaluation corroborated these findings, demonstrating medial hypercellularity, elastic fiber fragmentation, and adventitial fibrosis enriched within the -p.Met49Thr specimen. Taken together, these findings implicate a novel pathogenic variant that drives transcriptional reprogramming and proliferative VSMC remodeling, supporting that -associated aortopathy progression occurs via functional cell state transitions. Additionally, this work demonstrates the feasibility of FFPE-compatible snRNA-Seq for clinical variant annotation.