NM_005026.5(PIK3CD):c.1642C>T (p.Arg548Trp) is a missense variant causing substitution of arginine by tryptophan at amino acid 548. Another missense variant in the same codon, NM_005026.5(PIK3CD):c.1643G>A (p.Arg548Gln), has been reported in association with immunodeficiency 14 (SCV002301644.3) but has been classified as a VUS by the ClinGen Antibody Deficiencies VCEP, so PM5 is not met. This variant is present in gnomAD v4.1.0 at a total combined allele frequency of 0.00003730, with 60 alleles / 1,608,744 total alleles across all populations of gnomAD, which is higher than the ClinGen Antibody Deficiencies VCEP PM2_Supporting threshold of <0.00000132. The variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.0001338, with 3 alleles / 6,074 total alleles in the Middle Eastern population, which is lower than the BS1 threshold of >0.000316, so no population code can be applied. This variant has been reported in 1 affected proband with a phenotype including recurrent fever, neurodevelopmental abnormalities (0.5 pts), and diarrhea (1 pt), which are not sufficient to meet the phenotype requirements for inclusion of the proband in PS4_Supporting (1.5 total points, ClinVar Accession #: SCV002524004.1). The computational predictor REVEL gives a score of 0.349, which is below the ClinGen Antibody Deficiencies VCEP threshold of >0.644 and does not predict a damaging effect on PIK3CD function. The computational predictor CADD gives a PHRED score of 29.0, which is above the ClinGen Antibody Deficiencies VCEP threshold of >25.3 and predicts a deleterious effect on PIK3CD function. Because the two predictors do not agree on a damaging effect, the PP3 code is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant immunodeficiency 14 based on the ACMG/AMP criteria applied, as specified by the ClinGen Antibody Deficiencies VCEP: None. (VCEP specifications version 1.0.0).