The concept of receptor-mediated trafficking of secretory cargo through small coated vesicles is well established, with notable examples including clathrin, COPI, and COPII vesicles. Clathrin-coated vesicles function at the late Golgi apparatus and the plasma membrane, while COPI vesicles facilitate retrograde transport from the Golgi to the endoplasmic reticulum (ER). In contrast, COPII vesicles are responsible for the anterograde export of newly synthesized cargo from the ER. However, a significant challenge persists in understanding how cells secrete large cargoes, such as collagens, mucins, lipoproteins, and antibodies, which lack specific receptors and exceed the size capacity of conventional 60 nm COPII vesicles. Our groundbreaking discovery of TANGO1 and its associated proteins, cTAGE5 and TANGO1-short, sheds light on this intricate process. Unlike the traditional COPII mechanism, TANGO1 forms a transient tunnel between the ER and subsequent secretory compartments, thereby bypassing the necessity for vesicular intermediates. We have identified two classes of mutations in TANGO1. Class 1 mutations result in a complete gene deletion, leading to fetal demise at approximately 14 weeks of gestation. Class 2 mutations involve the production of a spliced variant that diminishes the export of collagens. Patients exhibiting these mutations often present with short stature, skeletal and dermal abnormalities, and signs of intellectual disability. Our research has revealed the existence of two distinct exit portals at the ER for the export of secretory cargo. Bulky collagens are restricted to approximately 40% of these exit sites, whereas smaller cargoes can exit through any available gate. Moreover, targeting TANGO1 presents promising potential for regulating hypercollagen secretion, with significant implications for the treatment of conditions such as scleroderma and the enhancement of wound healing in model organisms. This discovery not only advances our understanding of cellular secretion mechanisms but also opens new avenues for therapeutic interventions in collagen-related disorders.