Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders.

encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous missense variants that presented with developmental delay, intellectual disability, and movement disorders. Functional evaluation in revealed that all variants tested were damaging to gene function via a dominant negative genetic mechanism. Biochemical and proteomics studies showed a marked reduction in complex V abundance and activity in proband-derived blood cells and fibroblasts. Mitochondrial physiology studies in fibroblasts revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP levels indicative of uncoupled oxidative phosphorylation as a pathophysiologic mechanism. Our findings contrast functionally and clinically with the previously reported variant, p.Arg207His, suggesting a distinct pathological mechanism. This study therefore expands the phenotypic and genotypic spectrum of -associated conditions and highlights how functional studies can provide understanding of the genetic, molecular, and cellular mechanisms of variants of uncertain significance. With 12 heterozygous individuals now reported, is the most frequent nuclear genome cause of complex V deficiency.