Mutation of R691 at the interface between helices α5–7 and the Ptase core inactivates SHIP likely due to structural destabilization (Table 3, Figure 7—figure supplement 1B), and similar inactivating mutations at this interface have been associated with opsismodysplasia (P659S and W688C) and protection from diabetes (L632I) (Huber et al., 2013; Kagawa et al., 2005). Here, INPP5D is linked to diabetes mellitus.