Germline variants that disrupt components of the epigenetic machinery cause syndromic neurodevelopmental disorders. Using exome and genome sequencing, we identified de novo variants in KDM2A, a lysine demethylase crucial for embryonic development, in 18 individuals with developmental delays and/or intellectual disabilities. The severity ranged from learning disabilities to severe intellectual disability. Other core symptoms included feeding difficulties; growth issues, such as intrauterine growth restriction, short stature, and microcephaly; and recurrent facial features, such as epicanthic folds, upslanted palpebral fissures, thin vermillion of the lips, and low-set ears. Expression of human disease-causing KDM2A variants in a Drosophila melanogaster model led to neural degeneration, motor defects, and reduced lifespan. Interestingly, pathogenic variants in KDM2A affected physiological attributes, including subcellular distribution, expression, and stability in human cells. Genetic epistasis experiments indicated that KDM2A variants act via a dual mechanism-loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes. Data from enzymatic-methylation sequencing support the suggested gene-disease association by showing aberrant methylome profiles in affected individuals' peripheral blood. Combining our genetic, phenotypic, and functional findings, we establish de novo variants in KDM2A as causative for a syndromic neurodevelopmental disorder.