NM_005235.2:c.2371A>G (p.Thr791Ala) is a missense variant in exon 20 of ERBB4. It is present at extremely low frequency in population databases (gnomAD v2.1: 3/251,416 alleles, AF=0.00119%; gnomAD v4.1: 24/1,614,034 alleles, AF=0.00149%) with no homozygotes observed, meeting PM2 at supporting strength.¹ Multiple computational predictors support a benign interpretation: REVEL score of 0.321 is below the pathogenic threshold, BayesDel score of -0.090 is in the benign range, and SpliceAI predicts no splice impact (max delta = 0.00). BP4 is met at supporting strength.² This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (LabCorp, Ambry Genetics), each with criteria provided as a single submitter. No expert panel review has been performed.³ No functional studies, segregation data, de novo observations, case-control studies, or family co-segregation data are available for this variant. The variant lies within the ERBB4 kinase domain but is not located in a recognized mutational hotspot.⁴ Applying the generic ACMG/AMP 2015 final classification rules (PMID:25741868): one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in an overall classification of Uncertain Significance. The evidence is balanced and insufficient to classify this variant as either likely pathogenic or likely benign.⁵