Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterised. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in three pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2,042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5,422 controls. Eleven cases harboured 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included five high-impact variants predicted to prevent CalDAG-GEFI expression and six missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbβ3 signalling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical and dental bleeding from childhood, requiring at least one blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to ADP and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a non-syndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation.