CALR3 (calreticulin 3) is a testis-specific endoplasmic reticulum chaperone protein that plays a critical role in male fertility. During spermatogenesis, CALR3 functions as a lectin-independent chaperone for specific client proteins such as ADAM3 and is essential for sperm zona pellucida (ZP) binding 1. The protein exhibits calcium-binding capacity, though likely lower than the ubiquitous calreticulin (CALR), and localizes to the endoplasmic reticulum lumen where it participates in protein folding and ERAD pathway processes 2. Biallelic CALR3 mutations cause male factor infertility through disrupted sperm-ZP binding and acrosomal ultrastructural defects, preventing gamete fusion and oocyte activation 1. Notably, CALR3 is confined to testicular tissue in normal individuals and is not expressed in cardiomyocytes, making it an unlikely monogenic cause of cardiomyopathy despite previous inclusion in cardiomyopathy gene panels 2. While CALR3 has been examined as a cancer-testis antigen target for immunotherapy in lung and breast cancers, it showed no expression in these tumors and could not be induced by DNA methyltransferase inhibitors, limiting its therapeutic potential in these malignancies 3. Clinically, ICSI (intracytoplasmic sperm injection) represents an effective treatment for CALR3-deficient male infertility 1, providing personalized therapeutic options for affected patients.