NM_005475.2:c.127C>T (p.Arg43Cys) is a missense variant in SH2B3, a gene for which loss of function is a supported germline disease mechanism in myeloid and myeloproliferative disorders.¹ This variant is present in gnomAD v4.1 at a total allele frequency of 0.045% (695/1,540,252 alleles) and in v2.1 at 0.024% (41/172,716 alleles), with no homozygotes observed. The highest subpopulation frequency is 0.059% in the European (non-Finnish) population. These frequencies fall below the 0.1% threshold for PM2 at supporting level.² Multiple in silico tools predict a benign effect: REVEL score 0.254 (below pathogenic threshold), BayesDel score -0.346 (predicts benign), and SpliceAI max delta 0.00 (no splicing impact). This meets BP4 at supporting benign level.³ This variant is classified as Uncertain significance in ClinVar (1 submitter, GeneDx). OncoKB reports an Unknown Oncogenic Effect with no variant-specific curated functional evidence. No publications specifically mentioning NM_005475.2:c.127C>T were identified.⁴ With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced toward neither pathogenic nor benign. Under generic ACMG/AMP 2015 combination rules, this does not meet the threshold for Likely Pathogenic, Likely Benign, Pathogenic, or Benign. The variant remains a Variant of Uncertain Significance.⁵