NM_080605.4:c.901_904dup is a frameshift variant in B3GALT6 predicted to alter the C-terminus (p.Arg302GlnfsTer142). B3GALT6 loss of function is a well-established disease mechanism for autosomal recessive spondylodysplastic Ehlers-Danlos syndrome. PVS1 is applied at strong strength, downgraded from very_strong due to the 3' location (codon 302/330) and confirmed NMD escape in this single-exon gene (PMC6185798).¹ The variant is extremely rare in population databases, meeting PM2_Supporting: gnomAD v2.1 allele frequency 7.17e-06 (1/139,512 alleles) and gnomAD v4.1 allele frequency 9.06e-06 (14/1,544,998 alleles), both well below the 0.1% threshold. No homozygotes are observed.² The variant is present in ClinVar (Variation ID 1323966) with four clinical testing submissions: two classify it as Likely Pathogenic and two as Uncertain Significance. No expert panel review is available, and the cited PubMed references (PMID:25741868, PMID:28492532) are methodology guidelines that do not specifically mention this variant.³ SpliceAI predicts no significant splicing impact (max delta score 0.03). In silico missense predictors (REVEL, BayesDel) are not applicable to this frameshift variant. PP3 is not met; BP4 is not met given insufficient benign computational evidence.⁴ Applying generic ACMG/AMP 2015 final classification rules (PMID:25741868): with one strong pathogenic criterion (PVS1_Strong) and one supporting pathogenic criterion (PM2_Supporting), the variant does not reach the threshold for Likely Pathogenic (requires 1 Strong + 1–2 Moderate OR 1 Strong + 2 Supporting). The variant is classified as a Variant of Uncertain Significance (VUS). Additional evidence, particularly verified publication reports of the variant in affected individuals (PS4/PM3) and segregation data (PP1), may upgrade the classification upon human curator review.⁵