The NM_000552.5(VWF):c.4225G>T variant in VWF is a missense variant predicted to cause substitution of valine by phenylalanine at amino acid 1409. This variant has been reported in at least 3 apparently unrelated probands exhibiting a VWD Type 2M phenotype (PMID: 28971901 and PMID: 19404524, PS4_Moderate). The two probands of PMID: 28971901, exhibit excessive mucocutaneous bleeding as well as a laboratory phenotype of normal multimers, low VWF:RCo/VWF:Ag ratio and low collagen binding, which together are specific for VWD type 2M (PP4_Moderate). Low FVIII activity, an inconsistent phenotype, was also reported in these patients. The variant has been reported to segregate with VWD type 2M through at least 2 affected meioses from 2 different families (PP1_Moderate; PMID: 28971901). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.722, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The computational splicing predictor SpliceAI indicates that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PP1_Moderate, PP3, PM2_Supporting, PS4_Moderate, PP4_Moderate.