The NM_000552.5:c.4138A>G variant in VWF is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1380. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1164 (based on 8878/74958 alleles in the African/African American population, including 541 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. This variant has been observed in 1 VWD Type 2B patient with an alternate molecular basis for disease, the presence (with unreported phase) of the p.Arg1341Gln variant, previously classified Pathogenic for VWD Type 2B by the ClinGen VWD Type 2 VCEP (BP5; PMID: 30817071). At least 16 healthy adult individuals harboring the p.Asn1435Ser variant were found to be unaffected, with no diagnosis of a bleeding disorder and normal lab values, including bleeding scores lower than 4, VWF:RCo/VWF:Ag ratios >0.6, and no increased response to low-dose ristocetin (PMID: 20231421). The mean VWF:RCo/VWF:Ag ratio of 0.71-0.77 within this group was significantly reduced compared to 0.91-0.97 for WT, but within the normal range. However, BS2 was not considered due to incomplete penetrance in this gene-disease relationship. The computational predictor REVEL gives a score of 0.098, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant is classified as Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP4, BP5.