Three genes encoding identical calmodulin proteins show surprisingly different roles in brain development, with Calm1 uniquely controlling the migration of layer 4 cortical neurons while Calm2 and Calm3 cannot compensate for its loss. Loss of Calm1 or Calm2 additionally disrupts neuronal identity specification in this critical sensory processing layer. This challenges the assumption that identical proteins from different genes function interchangeably in cellular processes. Layer 4 neurons form the primary input gateway for sensory information in the cerebral cortex, making their proper positioning essential for normal sensory processing and cognitive function. The research advances our understanding of how subtle genetic differences can have profound developmental consequences, even when gene products appear identical. These findings may help explain certain neurodevelopmental disorders where cortical layering is disrupted, potentially including autism spectrum disorders and intellectual disabilities. The work also highlights how calcium signaling pathways, fundamental to many cellular processes, are fine-tuned through gene-specific rather than protein-specific mechanisms. While conducted in animal models, the results suggest that therapeutic approaches targeting brain development disorders may need to consider gene-specific rather than protein-specific interventions.