SYNPO2L is an actin-associated protein localized to the sarcomere that plays multifaceted roles in cardiac and cancer biology. Functionally, SYNPO2L modulates actin-based cytoskeletal organization and promotes stress fiber assembly through positive regulation of Rho signaling and actin filament bundling 1. In cardiac development and function, SYNPO2L variants are implicated in heart failure pathogenesis, with functional analysis of non-CAD-associated heart failure loci identifying SYNPO2L as a gene involved in cardiac development 2. SYNPO2L is also a major atrial fibrillation (AF) susceptibility gene at the chromosome 10 locus 1. Multiple transcript isoforms exist, including two that encode long noncoding RNAs and two that encode sarcomeric proteins; risk alleles are associated with decreased cardiac development genes and increased SYNPO2L lncRNA expression 1. Common missense variants in SYNPO2L associate with both AF and blood pressure regulation 3, 4. Beyond cardiac function, SYNPO2L exhibits oncogenic properties in colorectal cancer, where its mRNA stability is regulated by the m6A methyltransferase METTL16, and it promotes cancer cell metastasis by regulating COL10A1 secretion and facilitating epithelial-mesenchymal transition 5. Clinically, SYNPO2L represents a shared genetic locus between atrial fibrillation and heart failure pathogenesis 6.