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Protein phosphatase 2 regulatory subunit B56δ related neurodevelopmental disorder (PPP2R5D‐related NDD) is largely caused by de novo heterozygous missense PPP2R5D variants. We report medical characteristics, longitudinal adaptive functioning, and in‐person neurological, motor, cognitive, and electroencephalogram (EEG) activity for PPP2R5D‐related NDD. Forty‐two individuals (median age 6 years, range = 0.8–25.3) with pathogenic/likely pathogenic PPP2R5D variants were assessed, and almost all variants were missense (97.6%) and de novo (85.7%). Common clinical symptoms were developmental delay, hypotonia, macrocephaly, seizures, autism, behavioral challenges, and sleep problems. The mean Gross motor functional measure‐66 was 60.2 ± 17.3% and the mean Revised upper limb module score was 25.9 ± 8.8. The Vineland‐3 adaptive behavior composite score (VABS‐3 ABC) at baseline was low (M = 61.7 ± 16.8). VABS‐3 growth scale value scores increased from baseline in all subdomains (range = 0.6–5.9) after a mean follow‐up of 1.3 ± 0.3 years. EEG beta and gamma power were negatively correlated with VABS‐3 score; p < 0.05. Individuals had a mean Quality‐of‐life inventory‐disability score of 74.7 ± 11.4. Twenty caregivers (80%) had a risk of burnout based on the Caregiver burden inventory. Overall, the most common clinical manifestations of PPP2R5D‐related NDD were impaired cognitive, adaptive function, and motor skills; and EEG activity was associated with adaptive functioning. This clinical characterization describes the natural history in preparation for clinical trials. [ABSTRACT FROM AUTHOR]