Background <p>Mutations in the neuronal Na⁺/K⁺-ATPase subunit ATP1A3 are linked to a spectrum of neurological disorders, including rapid-onset dystonia-parkinsonism (RDP), yet their pathogenic mechanisms remain incompletely understood. We describe the complex clinical characteristics of a patient with early-onset movement disorders and a likely pathogenic de novo variant in ATP1A3(c·2438C&gt;T, p.A813V).</p> Methods <p>We identified a de novo heterozygous ATP1A3 p.A813V variant in a patient with clinically confirmed RDP and employed an integrative approach combining molecular dynamics (MD) simulations, zebrafish models, and patient-derived induced neurons (iNeurons) to delineate its pathogenesis.</p> Results <p>MD simulations revealed that the p.A813V substitution structurally distorts transmembrane helix packing, reduces structural stability, and diminishes water accessibility at the cation-binding site, predicting impaired Na⁺/K⁺-ATPase function. In vivo, <i>atp1a3b</i> knockout zebrafish developed pronounced neuronal hyperexcitability—reflected by elevated <i>c-fos</i> and pERK expression—that emerged before overt neurodegeneration, motor axonopathy, and neuromuscular junction defects. Complementarily, neurons expressing ATP1A3-p.A813V displayed significantly prolonged calcium transient decay times, suggesting a potential mechanism of altered Ca²⁺ handling and delayed clearance mechanisms compatible with ATP1A3 dysfunction. Consistent with these findings, patient-derived iNeurons exhibited markedly reduced ATP1A3 protein abundance and Na⁺/K⁺-ATPase activity.</p> Conclusions <p>Together, these findings lead us to propose a mechanistic model in which ATP1A3 dysfunction disrupts Ca²⁺ homeostasis, triggers neuronal hyperexcitability, and culminates in progressive neurodegeneration. This work provides a molecular and functional framework for targeting ionic and calcium homeostasis as a promising therapeutic strategy for ATP1A3-related disorders.</p>