TNFAIP3 variants show estimated prevalence of 1:2,800 in U.S. autoimmune disease cohorts

Background Monogenic diseases are considered rare, yet many remain underdiagnosed when clinical manifestations are heterogeneous. A20 haploinsufficiency (HA20) is an early-onset inborn error of immunity (IEI) caused by heterozygous germline TNFAIP3 variants, resulting in dysregulated inflammatory signaling and diverse immune phenotypes. Methods We analyzed variants in all human haploinsufficiency disease genes in gnomAD v4, applying refined loss-of-function predictors to estimate population frequencies. We assessed rare TNFAIP3 variants (allele frequency <0.01%) in All of Us (AoU), UK Biobank (UKBB), and gnomAD. Variants were classified as predicted loss-of-function (pLOF) or high predicted pathogenic missense (HPPM). Clinical associations were tested through phenome-wide association studies (PheWAS) and validated in a University of Pittsburgh referral cohort. Findings High-confidence deleterious variants in human haploinsufficiency disease genes, including IEI haploinsufficiency genes, occur frequently at the population level despite strong constraint. Across datasets, TNFAIP3 pLOF variants corresponded to estimated prevalences of ~1:14,400 (U.S.) and ~1:23,700 (global); combined pLOF + HPPM prevalences were ~1:2,800 (U.S.) and ~1:4,900 (global). PheWAS linked rare TNFAIP3 variants to immune phenotypes with large effect sizes. In a referral cohort (18 patients, 9 families), missense variants conferred hypomorphism with intermediate immunophenotypes. Interpretation Deleterious TNFAIP3 variants are over 100-fold more common than reported cases suggest and are associated with immune dysregulation spanning variable expressivity and severity. These findings establish proof-of-concept that haploinsufficiency diseases may be pervasively underrecognized. Patients with early-onset or treatment-refractory autoimmune disease should be considered for genetic testing, as precision therapies are available and commercial panels already incorporate TNFAIP3.