SETBP1 encodes a DNA-binding protein that regulates gene expression by recruiting epigenetic complexes that modify chromatin and by interacting with SET domain-containing proteins involved in histone methylation. It also binds the SET protein, an inhibitor of the phosphatase PP2A, and its activity supports cell growth and self-renewal in blood cells. Germline mutations in SETBP1 cause Schinzel-Giedion syndrome, a congenital disorder marked by neurological symptoms and an increased risk of malignancy. Somatic mutations in SETBP1 that disrupt its normal degradation are associated with blood cancers including myeloproliferative neoplasms and atypical chronic myeloid leukemia, indicating a role as an oncogene.

SETBP1 germline mutations cause Schinzel-Giedion syndrome, typically missense changes clustered in a narrow degron hotspot, and somatic mutations that disrupt degradation are linked to blood cancers. This missense variant at residue 384 lies outside that hotspot, is present in population databases (up to 0.167% in South Asians), and shows benign-leaning computational predictions, but no functional or clinical evidence yet establishes its effect. It therefore remains a variant of uncertain significance pending further clinical data.