PPP3CA encodes the catalytic alpha subunit of calcineurin, a calcium-dependent, calmodulin-stimulated protein phosphatase essential for transducing intracellular Ca2+-mediated signals 1. The enzyme dephosphorylates numerous substrates containing PxIxIT and LxVP motifs, including transcription factors (NFATC1, ELK1, TFEB), cytoskeletal proteins (cofilin via SSH1), and signaling molecules (DARPP32, KLHL3) 1. PPP3CA functions in the calcineurin-NFAT signaling cascade, promoting nuclear translocation of NFAT transcription factors to regulate gene expression 1. Physiologically, it is required for kidney development and function, salivary gland secretion, keratinocyte differentiation, and bone cell differentiation; it also regulates sleep-wake cycles as a sleep-promoting phosphatase competing with PKA at excitatory post-synapses 2. Pathogenic PPP3CA variants cause rare developmental and epileptic encephalopathy (DEE), with phenotype severity dependent on mutation type and location 3. Truncating mutations and variants in the regulatory domain produce drug-resistant early-onset epilepsy with developmental impairment, while calmodulin-binding domain variants cause milder childhood-onset seizures 3. Alternative splicing isoforms show CNS tissue-specificity and may influence disease manifestations 4. PPP3CA alterations also associate with multi-organ fibrosis pathogenesis 5 and cerebrospinal fluid proteomic changes in Alzheimer's disease 6. Overall, PPP3CA dysfunction impairs calcium-dependent signaling across multiple physiological systems.