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Abstract Background Protein phosphatase 2 regulatory subunit B’ Delta (PPP2R5D)-related neurodevelopmental disorder is a rare genetic condition caused by pathogenic variants in the PPP2R5D gene. Clinical signs include hypotonia, gross motor delay, intellectual disability (ID), epilepsy, speech delays, and abnormal gait among other impairments. As this disorder was recognized within the last decade, there are only 103 people published diagnoses to date. A thorough understanding of the motor manifestations of this disorder has not yet been established. Knowledge of the natural history of PPP2R5D related neurodevelopmental disorder will lead to improved standard of care treatments as well as serve as a baseline foundation for future clinical trials. Appropriate outcome measures are necessary for use in clinical trials to uniformly measure function and monitor potential for change. The aim of this study was to validate the gross motor function measure (GMFM) in children and adults with PPP2R5D-related neurodevelopmental disorder in order to better characterize the disorder. Results Thirty-eight individuals with PPP2R5D pathogenic variants, median age 8.0 years (range 1–27) were evaluated. Gross motor, upper limb and ambulatory function were assessed using the GMFM-66, six-minute walk test (6MWT), 10-meter walk run (10MWR), timed up and go (TUG), and revised upper limb module (RULM). The pediatric disability inventory computer adapted test (PEDI-CAT) captured caregiver reported assessment. Median GMFM-66 score was 60.6 (SD = 17.3, range 21.1–96.0). There were strong associations between the GMFM-66 and related mobility measures, 10MWR (rs = −0.733; p < 0.001), TUG (rs= −0.747; p = 0.003), 6MWT (r = 0.633; p = 0.006), RULM (r = 0.763; p < 0.001), PEDICAT-mobility (r = 0.855; p < 0.001), and daily activities (r = 0.822; p < 0.001) domains. Conclusions The GMFM is a valid measure for characterizing motor function in individuals with PPP2R5D related neurodevelopmental disorder. The GMFM-66 had strong associations with the RULM and timed function tests which characterized gross motor, upper limb and ambulatory function demonstrating concurrent validity. The GMFM-66 was also able to differentiate between functional levels in PPP2R5D related neurodevelopmental disorder demonstrating discriminant validity. Future studies should examine its sensitivity to change over time, ability to identify sub-phenotypes, and suitability as an outcome measure in future clinical trials in individuals with PPP2R5D variants.