One hurdle in the development of zebrafish models of human disease is the presence of multiple zebrafish orthologs resulting from whole genome duplication in teleosts. Mutations in inositol polyphosphate 5-phosphatase K (INPP5K) lead to a syndrome characterized by variable presentation of intellectual disability, brain abnormalities, cataracts, muscle disease, and short stature. INPP5K is a phosphatase acting at position 5 of phosphoinositides to control their homeostasis and is involved in insulin signaling, cytoskeletal regulation, and protein trafficking. Previously, our group and others have replicated the human phenotypes in zebrafish knockdown models by targeting bothINPP5Korthologsinpp5kaandinpp5kb. Here, we show thatinpp5kais the more closely related orthologue to humanINPP5K.While bothinpp5kaandinpp5kbmRNA expression levels follow a similar trend in the developing head, eyes, and tail,inpp5kais much more abundantly expressed in these tissues thaninpp5kb. In situ hybridization revealed a similar trend, also showing unique localization ofinpp5kbin the pineal gland and retina indicating different transcriptional regulation. We also found thatinpp5kbhas lost its catalytic activity against its preferred substrate, PtdIns(4,5)P2. Since most human mutations are missense changes disrupting phosphatase activity, we propose that loss ofinpp5kaalone can be targeted to recapitulate the human presentation. In addition, we show that the function ofinpp5kbhas diverged frominpp5kaand may play a novel role in the zebrafish.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00427-023-00703-z.