CASK (Ca2+/calmodulin-activated serine kinase) is a synaptic protein that interacts with the cytosolic tail of adhesion molecules such as neurexins, syncam and syndecans. It belongs to the MAGUK (membrane-associated guanylate kinase) family of scaffolding proteins which are known to decorate cell–cell junctions. CASK is an essential gene in mammals, critical for neurodevelopment. Mutations in the CASK gene in humans result in phenotypes that range from intellectual disability to lethality. Despite its importance, CASK has a single genetic isoform located in the short arm of the X chromosome near an evolutionary breakpoint. Surprisingly, CASK is a non-essential gene in invertebrates and displays functional divergence. In the present article, we describe the phylogenetic differences in existing CASK orthologues. The CASK gene has undergone a huge expansion in size (~55-fold). Almost all of this expansion is a direct result of an increase in the size of the introns. The coding region of CASK orthologues, and hence the protein, exhibit a high degree of evolutionary conservation. Within the protein, domain arrangement is completely conserved and substitution rates are higher in the connecting loop regions [L27 (Lin2, Lin7)] than within the domain. Our analyses of single residue substitutions and genotype–phenotype relationships suggest that, other than intronic expansion, the dramatic functional changes of CASK are driven by subtle (non-radical) primary structure changes within the CASK protein and concomitant changes in its protein interactors.

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