Homozygous or compound heterozygous mutations in solute carrier family 34, member 3 ( SLC34A3 ) cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Patients heterozygous for SLC34A3 pathogenic variants may be at increased risk for renal calcification but reports have been mostly limited to family members of patients with autosomal recessive HHRH. To determine the phenotypic spectrum of SLC34A3 Ser192Leu, we examined the most pathogenic SLC34A3 variant Ser192Leu (238 out of 174,417 participants) in an unselected, health system-based research cohort in central and northeast Pennsylvania. SLC34A3 Ser192Leu heterozygotes had higher risks of nephrolithiasis ICD diagnosis (13% vs. 6%), hypophosphatemia <2.5 mg/dL (31/96 [32%] vs. 6226/39636 [16%]), lower eGFR (−4.43, 95% CI: −7.03, −1.83; p=0.001) and tended to have higher prevalence of kidney/liver cyst ICD codes (5% vs. 3%; p=0.09), compared to controls. Further studies are needed to determine whether personalized approaches (i.e. phosphate supplementation) to patients heterozygous for SLC34A3 pathogenic variants can reduce kidney stone burden and risk of kidney function decline. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The patient enrollment and exome sequencing were funded by the Regeneron Genetics Center. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committee/IRB of Geisinger Medical Center gave ethical approval for this work, and participants completed informed consent in the Geisinger MyCode/DiscovEHR study I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are available upon reasonable request to the authors and subject to a data use agreement.