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Significance The Rab5 GTPase functions in early endosome (EE) fusion in the endocytic pathway. Here, we propose that RAB5B also has a noncanonical vesicular fusion function in the regulated secretion pathway that produces mature surfactant proteins SP-B and SP-C in the lung. This function was revealed from investigation of a proband with interstitial lung disease suggestive of a surfactant dysfunction disorder who carried a de novo Asp136His variant in the RAB5B gene. Our modeling in C. elegans provided information on the genetic and cell biological mechanism, and analyses of proband and normal lung biopsies suggested a function for RAB5B and EEs in surfactant protein processing/trafficking. This work indicates that RAB5B p.Asp136His causes a surfactant dysfunction disorder.