The human synapse proteome is a highly complex collection of proteins that is disrupted by hundreds of gene mutations causing over 100 brain diseases. These synaptic diseases, or synaptopathies, cause major psychiatric, neurological and childhood developmental disorders through mendelian and complex genetic mechanisms. The human postsynaptic proteome and its core signaling complexes built by the assembly of receptors and enzymes around Membrane Associated Guanylate Kinase (MAGUK) scaffold proteins are a paradigm for systematic analysis of synaptic diseases. In humans, the MAGUK Associated Signaling Complexes are mutated in Autism, Schizophrenia, Intellectual Disability and many other diseases, and mice carrying orthologous mutations show relevant cognitive, social, motoric and other phenotypes. Diseases with similar phenotypes and symptom spectrums arise from disruption of complexes and interacting proteins within the synapse proteome. Classifying synaptic disease phenotypes with genetic and proteome data provides a new brain disease classification system based on molecular etiology and pathogenesis.