In vitro modeling is a powerful approach to investigate the pathomechanisms driving human congenital conditions. Here we use human embryonic stem cells (hESCs) to model Nager and Rodriguez syndromes, two craniofacial conditions characterized by hypoplastic neural crest-derived craniofacial bones, caused by pathogenic variants of SF3B4, a core component of the spliceosome. We observed that siRNA-mediated knockdown of SF3B4 interferes with the production of hESC-derived neural crest cells, as seen by a marked reduction in neural crest gene expression. This phenotype is associated with an increase in neural crest cell apoptosis and their premature neuronal differentiation. Together, these results point at a role of SF3B4 in neural crest cell survival, maintenance, and differentiation as the primary cause of Nager/Rodriguez syndrome associated craniofacial defects, and illustrate the benefit of in vitro human stem cell models to understand congenital diseases.