Pathogenic variants in BTK gene are associated with X-linked agammaglobulinemia, characterized by the absence of immunoglobulins and B cells; it manifests as an inborn error of immunity from early childhood. Late onset is rare and causes a diagnostic odyssey.

We present a 32-year-old male who made his debut at the age of 22 with chronic diarrhea, recurrent sinusitis and 4 hospitalizations due to pneumonia. He was asymptomatic prior to his debut.

On physical examination, tonsils were observed without adenopathies or hepatosplenomegaly. At onset, immunoglobulins were documented with IgA <10 mg/dL, IgM G (p.Arg28Gly) was found by massive parallel and Sanger sequencing techniques in the proband and his mother.

According to the ACMG criteria, we classified the variant as likely pathogenic. However, since the variant was not previously reported, and due to the atypical phenotype of the proband, the biological effect of the variant on the protein is unknown. Therefore, in silico experiments were performed. Through the analysis of amino acid conservation, it was determined that it is highly conserved in different vertebrate species. In the structural comparison of the models generated by AlphaFold2, given the RMSD value obtained, there are changes in the structure as well as in the electrostatic potential that reveal alterations in the binding site. Up to this moment, our evidence suggests that there are changes in the protein. Additionally, docking analysis showed conserved interaction with the ligand in the binding site. In consequence, we could assume that this variant conserves a residual activity of the protein which could explain the atypical onset.