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DRG1 is a highly conserved member of a class of GTPases implicated in ribosome biogenesis and translation. The expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes including protein synthesis and cellular proliferation. Using exome sequencing, we identified rare and likely pathogenic germline DRG1 variants including three stop-gained p.Gly54*, p.Arg140*, p.Lys263* and a p.Asn248Phe missense variant. These alleles segregate recessively in four affected individuals from three unrelated families and cause a neurodevelopmental disorder with global developmental delay, microcephaly, short stature and craniofacial anomalies. Using functional assays, we show that these loss-of-function variants: 1) severely disrupt DRG1 mRNA/protein stability in patient-derived fibroblasts, 2) impair it’s GTPase activity in vitro and 3) compromise it’s binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of Drg1 in mice resulted in pre-weaning lethality. Our work highlights the importance of DRG1 GTPase activity for normal development and underscores the significance of translation factor GTPases in human physiology and homeostasis.