The ADNP syndrome, also known as Helsmoortel-Van der Aa syndrome (HVDAS), is an autosomal dominant neurodevelopmental disorder caused by heterozygous truncating variants abolishing the homeobox and/or HP1 domains of ADNP. Rare missense changes in the ADNP gene are usually variants of uncertain significance or reclassified as (likely) benign because they are inherited from an unaffected parent, and a causative role was documented for only three of them. We report a 24-year-old Italian woman presenting with intellectual disability, visual and severe speech impairment, microcephaly, truncal obesity, and hirsutism. Behavioral disturbance was significant and included fragmented sleep, self- and hetero-aggression, outbursts of anger, and verbal and physical violence crises. Additional unusual findings were hyperandrogenism and secondary amenorrhea. Next-generation sequencing showed the novel de novo missense variant c.2405C>T, p.(Ser802Phe) affecting the DNA-binding homeodomain of ADNP. In silico analysis revealed this variant is located in a genomic region highly intolerant to missense changes, and several tools predicted a deleterious effect on protein function. Counterintuitively to the known molecular pathogenesis for ADNP syndrome, calculation of the binding free energy and dissociation constant of the p.(Ser802Phe) missense substitution suggested a stronger ADNP-DNA interaction, thus opening the path to the hypothesis of a gain-of-function effect. This clinical report expands genotype-phenotype variability and correlations in ADNP syndrome.