Diverse neurodevelopmental syndromes (e.g. Fragile X) are caused by alterations in specific genes leading to pervasive impairments comorbid with autism (i.e. social and repetitive behaviors). Although all ASDs converge into common core behaviors, genetic variants in ASD are very heterogeneous. Here, we describe a cleavable cell adhesion molecule (Negr1) as upregulated in the brain of 5 diverse mouse models of ASDs (including Fragile X) and postmortem brains from people with autism or Fragile X, and causative of core ASD behaviors and brain alterations when up-regulated in wild-type (WT) animals in vivo. In particular, we found that Negr1 upregulation in the prefrontal cortex of WT mice was sufficient to induce disruptions in sociability, repetitive behaviors and neuronal morphology. Moreover, we found that overexpression of the soluble form of Negr1 in WT animals is sufficient to cause social deficits, but not repetitive behaviors. Supporting the relevance of the latter finding, we found that Negr1 is excessively cleaved in 2 diverse mouse models of ASD. Altogether, our results on the causal link between Negr1 upregulation and ASD core features in WT mice, together with our findings on Negr1 dysregulation in diverse ASD mouse models, may explain how a wide variety of ASD genetic variants converge into a unique core group of impaired processes during brain development. Our results also indicate regulation of Negr1 pathway as a possible target for future therapies and assessment of Negr1 levels in biological fluids as a potential biomarker for patient stratification in future clinical trials.