TMEM161B encodes a conserved multi-pass transmembrane protein with critical roles in both cardiac and neurological development. In the heart, TMEM161B regulates cardiac rhythm by modulating intracellular calcium ion handling and potassium/calcium currents in cardiomyocytes, essential for proper action potential repolarization 1. Mouse models show that Tmem161b loss-of-function causes developmental cardiac structural abnormalities and arrhythmias 2. In the central nervous system, TMEM161B functions as a regulator of neocortical development through multiple mechanisms. It modulates radial glial cell polarity and scaffolding via CDC42-Rho-GTPase signaling 3, and localizes to primary cilia where it regulates Sonic Hedgehog signaling critical for cortical gyration and patterning 4. Biallelic mutations in TMEM161B cause polymicrogyria with intellectual disability 534. Notably, ciliary dysfunction appears central to TMEM161B pathology, as null mice exhibit shortened and dysmorphic cilia in developing neural tissue 4. Clinically, TMEM161B variants represent variants of unknown relevance (VUR) in congenital heart disease 2, while specific SNP variants associate with major depressive disorder susceptibility 6. The protein's conserved function across fly, zebrafish, and mouse models underscores its fundamental developmental importance.