POPDC3 encodes a transmembrane protein containing a unique cyclic adenosine monophosphate (cAMP) binding domain, with highest expression levels in skeletal muscle 1. The protein functions as a cAMP effector involved in maintaining striated muscle homeostasis and regulating cellular signaling pathways 2. Mechanistically, POPDC3 modulates the mechano-gated potassium channel TREK-1, with pathogenic variants causing aberrant channel regulation 3. The protein plays crucial roles in skeletal muscle regeneration, heart rhythm control, and stress signaling 2. Disease relevance centers on limb-girdle muscular dystrophy type 26 (LGMD26), where homozygous missense variants in conserved regions cause autosomal recessive muscular dystrophy characterized by proximal muscle weakness, dystrophic muscle biopsies, and elevated serum creatine kinase levels 34. Additionally, POPDC3 functions as a tumor suppressor in various cancers, with downregulation associated with enhanced tumor cell proliferation, migration, and metastasis 25. Clinical significance includes its potential as a biomarker for muscular dystrophy diagnosis and as a therapeutic target in both muscle disorders and cancer, though its role in cancer appears context-dependent 16.