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Integrating structural and evolutionary data to interpret variation and pathogenicity in adapter protein complex 4

Genetic variation in the membrane trafficking adapter protein complex 4 (AP‐4) can result in pathogenic neurological phenotypes including microencephaly, spastic paraplegias, epilepsy, and other developmental defects. We lack molecular mechanisms responsible for impaired AP‐4 function arising from genetic variation, because AP‐4 remains poorly understood structurally. Here, we analyze patterns of AP‐4 genetic evolution and conservation to identify regions that are likely important for function and thus more susceptible to pathogenic variation. We map known variants onto an AP‐4 homology model and predict the likelihood of pathogenic variation at a given location on the structure of AP‐4. We find significant clustering of likely pathogenic variants located at the interface between the β4 and N‐μ4 subunits, as well as throughout the C‐μ4 subunit. Our work offers an integrated perspective on how genetic and evolutionary forces affect AP‐4 structure and function. As more individuals with uncharacterized AP‐4 variants are identified, our work provides a foundation upon which their functional effects and disease relevance can be interpreted.