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Single nucleotide variants (SNVs), particularly loss-of-function mutations, are significant contributors to autism spectrum disorder (ASD) risk. Here we report the first systematic deep sequencing study of 55 postmortem ASD brains for SNVs in 78 known ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering (26/55 cases versus 12/50 controls, p = 0.015), deleterious (16/55 versus 5/50, p = 0.016), or loss-of-function (6/55 versus 0/50, p = 0.028) compared to controls, with recurrent deleterious mutations in ARID1B, SCN1A, SCN2A, and SETD2, suggesting these mutations contribute to ASD risk. In several cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD and one Fragile X premutation case showed deleterious somatic mutations, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis.