Large-scale genomic analyses have identified hundreds of genes associated with neurodevelopmental disorders, often via heterozygous de novo mutations. To treat these disorders, we need to clarify whether they act via a loss-of-function or gain-of-function mechanism and how this correlates with phenotype. Looking at the mutations identified, many genes are enriched for protein-truncating variants, in keeping with a loss-of-function/haploinsufficiency model. In contrast, many other genes are enriched for missense variants often at recurrent loci, in keeping with a gain-of-function model. Through phenotype and functional analyses of the genes SCN2A and SLC6A1, an alternative explanation arises: that most variants are loss-of-function and a combination of protein vulnerability and hypermutable loci underlie missense enrichment and recurrence.