The NM_000552.5(VWF):c.4195C>T (p.Arg1399Cys) missense variant has been reported in a proband displaying excessive mucocutaneous bleeding as well as laboratory phenotypes of low VWF:RCo/VWF:Ag ratio (0.67), abnormal collagen binding assay, and normal high molecular weight multimer pattern, which together are highly specific for VWD type 2M (PP4_moderate, PMID: 28083987). Although the patient's multimer pattern did not lack high-molecular weight forms, it was visibly smeared, similar to those associated with the p.Arg1315Cys and p.Arg1374Cys variants (PMID: 26988807). At least 5 probands with phenotypes meeting at least the laboratory phenotype requirements of type 2M PP4 criteria, in addition to the proband used for the PP4_Moderate code (PS4; PMID: 17000885, PMID: 26988807, PMID: 35452508, PMID: 34758185). The computational predictor REVEL gives a score of 0.712, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The Grpmax allele frequency in gnomAD v4.1 is 0.00005281 (8/74886 alleles) in the African/African American population, which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). In summary, the variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease Type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Strong, PP4_Moderate, PP3, and PM2_Supporting. (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/13/2024)