Significance In humans, SEC23B deficiency results in congenital dyserythropoietic anemia type II, a disease of abnormal red blood cell development, while SEC23A deficiency results in cranio-lenticulo-sutural-dysplasia, a disease characterized by bone abnormalities due to defective collagen secretion (but no red blood cell defect). In this study, we show that SEC23A and SEC23B overlap in function, and that the disparate phenotypes of SEC23A/SEC23B deficiency within and across species are likely due to evolutionary shifts in gene-expression programs, rather than distinct functions of the SEC23 paralogs. Our studies provide a rationale for increased SEC23A or SEC23B expression as a therapeutic strategy for congenital dyserythropoietic anemia type II or cranio-lenticulo-sutural-dysplasia, respectively.