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Autism spectrum disorder (ASD) is more prevalent in males; however, the etiology for this sex bias is not well understood. Many mutations on X-linked cell adhesion molecule NLGN4X result in ASD or intellectual disability. NLGN4X is part of an X-Y pair, with NLGN4Y sharing ∼97% sequence homology. Using biochemistry, electrophysiology, and imaging, we show that NLGN4Y displays severe deficits in maturation, surface expression, and synaptogenesis regulated by one amino acid difference with NLGN4X. Furthermore, we identify a cluster of ASD-associated mutations surrounding the critical amino acid in NLGN4X, and these mutations phenocopy NLGN4Y. We show that NLGN4Y cannot compensate for the functional deficits observed in ASD-associated NLGN4X mutations. Altogether, our data reveal a potential pathogenic mechanism for male bias in NLGN4X-associated ASD. • Despite sharing ∼97% amino acid identity, NLGN4X and NLGN4Y are differentially regulated • NLGN4Y cannot traffic to the surface due to one amino difference from NLGN4X • A cluster of autism-associated variants in NLGN4X surrounds the critical amino acid • NLGN4X autism-associated variants display a deficit in trafficking similar to NLGN4Y NLGN4X and NLGN4Y are thought to have similar functions due to their ∼97% shared amino acid identity. Nguyen et al. demonstrate NLGN4Y has a deficit in trafficking due to one amino acid difference. The trafficking deficit phenotype is also found in a cluster of autism-associated variants in NLGN4X near the critical amino acid. [ABSTRACT FROM AUTHOR]