PPP1R3A encodes a glycogen-targeting regulatory subunit of protein phosphatase 1 (PP1) essential for regulating glycogen metabolism in skeletal muscle and cardiac tissue. As a PP1 regulatory subunit, PPP1R3A directs PP1 to glycogen synthase and calcium-handling proteins, facilitating glycogen synthesis and regulating sarcoplasmic reticulum calcium cycling 1. Loss of PPP1R3A function impairs glycogen synthesis and reduces muscle glycogen content by approximately 40-65% in carriers of truncating variants 1. PPP1R3A also associates with ryanodine receptor 2 (RyR2) and phospholamban in cardiac tissue, where it targets PP1 for dephosphorylation of these calcium-regulatory proteins 2. Clinically, PPP1R3A dysfunction contributes to multiple disease phenotypes. Genetic disruption promotes atrial fibrillation through impaired calcium handling and increased RyR2/phospholamban phosphorylation 2. In cardiac disease, PPP1R3A emerges as a central regulator whose network connectivity changes significantly in pressure-overload heart failure; mice lacking PPP1R3A are protected against this condition 3. PPP1R3A loss correlates with increased obesity, fat deposition, and insulin resistance 4. Additionally, PPP1R3A variants associate with lethal prostate cancer risk 5, diabetic nephropathy 6, and reduced hand grip strength 7. Notably, a frameshift mutation occurs in approximately 1 in 70 UK individuals, representing the first prevalent mutation directly impairing human glycogen synthesis 1.