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Urinary proteomics of 9 patients with DBS revealed that the urinary proteome of a DBS patient with the missense variant LRP2 p.C1400R was indistinguishable from that of patients with splice site, nonsense, or frameshift mutations. A CRISPR mouse model of the variant was generated to determine the mechanism of LoF and proteinuria. The mutant LRP2 was expressed and observed to dimerize and localize to the proximal tubule apical membrane. However, both fluid-phase and receptor-mediated endocytosis was impaired in the context of a general perturbation of endocytic flux. Immunofluorescence revealed aberrant endocytic recycling with mislocalized RAB11\n                    <jats:sup>+<\/jats:sup>\n                    and TFR1\n                    <jats:sup>+<\/jats:sup>\n                    compartments and enlarged lysosomes. Structural modeling showed that the LRP2 assembly likely tolerates the cysteine-to-arginine substitution at the cell surface, but at endosomal pH the variant introduced steric clashes that may disrupt intramolecular interfaces and disturb receptor recycling. 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