Armendarez, O. J.; Bower, D. Q.; Flynn, K. R.; Bergman, M. R.; Albertin, C. B.; Deravi, L. F.

As more genome libraries become accessible across multiple cephalopod species, long standing assumptions about the molecular basis of their dynamic optical systems are being revisited. For example, cephalopod-specific reflectin proteins now appear far more variable as newly annotated sequences diverge from the canonical features that have long defined this protein family. In this perspective, we discuss these nuances and introduce a theoretical framework that expands the reflectin domain classification while preserving specificity across 141 known and previously uncharacterized reflectin sequences from ten cephalopod species. By combining this broadened domain architecture with quantitative, bioinformatics driven metrics, we establish a generalizable framework that reliably identifies reflectins across their full sequence diversity, allowing for deeper structural comparisons and future functional discovery.