The NM_000531.6:c.264A>T variant in OTC is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 88 (p.Lys88Asn). One male patient with this variant developed hyperammonemic coma with 8 months of age. OTC enzymatic activity in liver tissue was reduced (3% wildtype) which is highly specific for OTC deficiency (PP4_Moderate, PMID 8260194). This variant has been reported in 2 additional probands with biochemical and clinical evidence of OTC deficiency (PS4_Moderate; PMID: 8956038, 25573644). Another patient with this variant have been reported in the literature, but clinical and biochemical features were not reported (PMID: 25433810). The highest population minor allele frequency in gnomAD v4.1 (Grpmax FAF was not available for this variant) is 0.000001127 (1/887338 alleles) in European (non-Finnish) population, with 1 hemizygotes across all populations. This is lower than the ClinGen UCD VCEP threshold (<0.000015 AND ≤1 hemizygotes) for PM2_Supporting, meeting this criterion (PM2_Supporting). Growth assay in yeast showed >65% and <80% of wild-type OTC growth activity, indicating that this variant does not impact protein function (PMID: 37146589, BS3_Supporting). The computational predictor REVEL gives a score of 0.88, which is between 0.773 and 0.932, evidence that correlates with moderate impact to OTC function (PP3_Moderate), additionally SpliceAI delta score is 0.24 for a loss of the canonical acceptor, and 0.18 for loss of the canonical donor of this exon. In summary, this variant meets the criteria to be classified as Likely Pathogenic for X-linked ornithine carbamoyltransferase deficiency. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic/benign evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Urea Cycle Disorders VCEP (OTC specifications version 1.0.0), 02/08/2025: PP4_Moderate (+2), PS4_Moderate (+2), PP3_Moderate (+2), PM2_Supporting (+1), BS3_Supporting (-1).