We recently found a significant association between exonic copy-number variations in the Rho GTPase activating protein 10 (Arhgap10) gene and schizophrenia in Japanese patients. Special attention was paid to one patient carrying a missense variant (p.S490P) in exon 17, which overlapped with an exonic deletion in the other allele, because two mutations in the same gene are considered a typical genetic model of severe schizophrenia. Accordingly, we generated a mouse model (ARHGAP10NHEJ/S490P mice) carrying a missense variant and a coexisting frameshift mutation (NHEJ). We examined the spatiotemporal expression of Arhgap10 mRNA in the brain and found the highest expression levels in the striatum and nucleus accumbens (NAc), followed by the frontal cortex in adolescent mice. The expression levels of phosphorylated myosin phosphatase-targeting subunit 1 and phosphorylated p21-activated kinases in the striatum and NAc were significantly increased in ARHGAP10NHEJ/S490P mice compared with WT littermates. ARHGAP10NHEJ/S490P mice exhibited a significant increase in neuronal complexity and spine density in the striatum and NAc. There was no difference in touchscreen-based visual discrimination (VD) learning between ARHGAP10NHEJ/S490P and WT mice, but a significant impairment of VD was evident in ARHGAP10NHEJ/S490P mice but not WT mice when they were treated with methamphetamine. The number of c-Fos-positive cells was significantly increased after methamphetamine treatment in the dorsomedial striatum and NAc core of ARHGAP10NHEJ/S490P mice. Taken together, these results suggested that schizophrenia-associated Arhgap10 gene mutations result in morphological abnormality in the striatum and NAc neurons, which may be associated with vulnerability of cognition to methamphetamine treatment.