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Objectives TNFRSF13B is among the most polymorphic genes in humans and other mammals and the encoded receptor (sometimes called ‘calcium-modulator and cyclophylin ligand interactor’ or TACI) determines the quality and pathogenicity of antibody responses. GWAS surveys of subjects with Systemic Lupus Erythematosus (SLE) associate TNFRSF13B with risk but the high TNFRSF13B polymorphism and broad impact of mutations on function of the receptor undermines the sensitivity of GWAS as a measure of impact. We reasoned that a first step in determining whether and how TNFRSF13B contributes to development of SLE, might involve the study of subjects of African American ethnicity that are associated with distinct frequencies of TNFRSF13B polymorphisms compared to frequencies in subjects of European or Chinese ethnicities.Methods We sequenced exons 3-5 in 303 SLE and 104 healthy control subjects, including a large proportion of individuals of African American ancestry, recruited as part of the Michigan Lupus Epidemiology and Surveillance (MILES) Cohort and Biorepository.Results We found that SLE subjects of African ethnicity had an almost a two fold increased frequency of subjects with two P151L alleles compared to the frequencies in the population of African ethnicity reported in GnomAD, v4.0.0. SLE subjects and none of the controls were compound heterozygotes, A181E/C104R, A181E/P251L, K188M/P251L, and R202C/P251suggesting an association of these variants with disease.Conclusions Although Clin Var data base classifies the P251L variant as benign, a full assessment of the mono or biallelic mutation consequences for TNFRSF13B function has not been reported. One could argue that two receptor disrupting variants such as A181E and C104R might impair the assembly of receptor trimers, with consequent functional deficiency. However, deficiency of TNFRSF13B expression and function appears protective in some animal models of SLE. How variants that are not thought to disrupt receptor signaling may be a risk factor for disease is not known and indicates the possibility that receptor signaling may not be the only function of TNFRSF13B.