LRRC37B is a hominid-specific gene encoding a receptor selectively localized to the axon initial segment (AIS) of human cortical pyramidal neurons, where it functions as a species-specific modifier of neuronal excitability 1. Mechanistically, LRRC37B binds to both the secreted ligand FGF13A and the voltage-gated sodium channel β-subunit SCN1B, concentrating inhibitory effects on Nav channel function to reduce neuronal excitability specifically at the AIS 1. Ectopic expression of LRRC37B in mouse cortical neurons in vivo reduces intrinsic excitability, a distinctive feature of human neurons, and electrophysiological recordings in human cortical slices confirm lower excitability in neurons expressing LRRC37B 1. Beyond its neurophysiological role, LRRC37B-containing low-copy repeats (LCRs) function as recombination hotspots in the human genome. LRRC37B pseudogenes within NF1-REPb and NF1-REPc repeats mediate nonallelic homologous recombination (NAHR) events, giving rise to recurrent NF1 microdeletions associated with neurofibromatosis type-1 23. These ~1.0-Mb type-3 NF1 deletions demonstrate the unusually high recombinogenic potential of LRRC37-containing sequences 3. LRRC37B thus links human genome evolution with specialized neuronal properties underlying enhanced cognitive abilities while simultaneously contributing to genomic instability at 17q11.2.