The study investigates the genetic architecture of autism spectrum disorder (ASD) by analyzing rare coding variations in 3,871 ASD cases and 9,937 ancestry-matched or parental controls using exome sequencing. The analysis identifies 22 autosomal genes with a false discovery rate (FDR) < 0.05 and a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of these genes encode proteins involved in synaptic, transcriptional, and chromatin remodeling pathways. The study also highlights the importance of integrating *de novo*, inherited, and case-control variation to identify ASD genes, and demonstrates that the impact of these genes on risk varies, with some having a large effect and others a smaller or no effect. The findings provide insights into the neurobiology of ASD and the genetic factors contributing to social communication and interaction deficits.The study investigates the genetic architecture of autism spectrum disorder (ASD) by analyzing rare coding variations in 3,871 ASD cases and 9,937 ancestry-matched or parental controls using exome sequencing. The analysis identifies 22 autosomal genes with a false discovery rate (FDR) < 0.05 and a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of these genes encode proteins involved in synaptic, transcriptional, and chromatin remodeling pathways. The study also highlights the importance of integrating *de novo*, inherited, and case-control variation to identify ASD genes, and demonstrates that the impact of these genes on risk varies, with some having a large effect and others a smaller or no effect. The findings provide insights into the neurobiology of ASD and the genetic factors contributing to social communication and interaction deficits.