rs33978901 — VWF p.Arg924Gln

The VWF R924Q Variant — A Quiet Modifier of Bleeding Risk

Von Willebrand factor (VWF) is the molecular glue of hemostasis — a large plasma protein that tethers platelets to damaged blood vessel walls and serves as the carrier and protector of coagulation Factor VIII (FVIII). The rs33978901 variant introduces a single amino acid change, replacing arginine with glutamine at position 924¹¹ replacing arginine with glutamine at position 924
p.Arg924Gln, encoded by c.2771G>A in the VWF coding sequence; the gene lies on the minus strand, so the plus-strand T allele corresponds to the coding-strand A allele. Unlike the dramatic pathogenic mutations in classical von Willebrand disease, this variant acts as a subtle modifier: in most carriers it causes no clinical problem, but in the wrong context — especially blood group O — it can push already-low VWF levels into a range that warrants medical attention.

The Mechanism

In vitro expression studies of recombinant p.R924Q VWF²² In vitro expression studies of recombinant p.R924Q VWF
Hickson et al. tested the variant protein in cell culture: no effect on VWF secretion, multimer structure, or FVIII binding was found showed no detectable functional defect. This means R924Q likely does not impair VWF protein directly but instead travels on a haplotype — a block of inherited variants³³ haplotype — a block of inherited variants
A haplotype is a set of alleles inherited together as a unit; the R924Q allele appears to tag a chromosomal background that is associated with reduced VWF production associated with lower VWF output. The biological mechanism is therefore quantitative (reduced VWF levels) rather than qualitative (abnormal protein structure or function).

The ABO blood group⁴⁴ ABO blood group
Encoded by the ABO gene on chromosome 9; the H antigen added to VWF by non-O blood groups increases its half-life and plasma concentration by protecting it from clearance independently controls VWF levels: blood group O individuals have VWF concentrations 25-35% lower⁵⁵ 25-35% lower
Consistently documented across multiple population studies; the mechanism involves reduced glycosylation protecting VWF from ADAMTS13 cleavage and macrophage clearance than non-O individuals. When R924Q-associated reduced production overlaps with blood group O's reduced half-life, the combined effect explains up to 35% of VWF variance⁶⁶ the combined effect explains up to 35% of VWF variance
Versus ~10% for the variant alone in controls not stratified by blood group — a clinically meaningful amplification.

The Evidence

The definitive study is Hickson et al. 2010⁷⁷ Hickson et al. 2010
Journal of Thrombosis and Haemostasis; 1,115 healthy controls and 148 von Willebrand disease index cases genotyped for c.2771G>A. Among 148 VWD index cases, the variant appeared in six; five of those six carried at least one additional VWF pathogenic mutation, indicating R924Q rarely causes VWD on its own but frequently appears as a co-factor. Among healthy controls, 35 heterozygous carriers were identified. Crucially, variance in VWF and FVIII levels attributable to the variant jumped from 10% overall to 35% in blood group O carriers — demonstrating strong epistatic amplification.

ClinVar (VCV000100240) reflects this nuanced picture: across 11 contributing submissions, classifications range from benign to uncertain significance, with no pathogenic calls. Major clinical laboratories (Mayo Clinic, ARUP, Quest Diagnostics) classify it as benign or likely benign in isolation. The variant's clinical relevance is context-dependent, not intrinsic.

Population frequency is low and strongly European-enriched: the T allele occurs at ~2.2% in Europeans and under 0.4% in African and South Asian populations, with near-absence in East Asians. This ancestry skew is consistent with a European founder haplotype.

Practical Actions

For most carriers, the variant is a monitoring signal rather than an emergency. The key practical step is baseline VWF antigen and FVIII activity measurement — this tells you whether levels are in the range where the variant is functionally relevant (typically VWF:Ag below 50 IU/dL or FVIII activity below 50%). If levels are normal, no further action is needed. If they are low-normal (50-100 IU/dL), tracking them is useful since acquired stressors (surgery, pregnancy, illness) can temporarily suppress VWF further. Carriers who also have blood group O should have this combination specifically noted, as the dual effect increases the probability that levels are measurably reduced.

Carriers contemplating surgery, tooth extraction, childbirth, or procedures involving significant bleeding risk should disclose this variant and have VWF/FVIII checked beforehand so that a hematologist can determine whether desmopressin (DDAVP) or VWF concentrate prophylaxis is warranted.

Interactions

The most clinically significant interaction is with ABO blood group O (rs505922 and related ABO loci). Blood group O reduces VWF levels 25-35% independently; the R924Q haplotype adds a further reduction, and together they account for up to 35% of VWF variance in carriers. This combination warrants specific clinical attention.

Any second pathogenic VWF variant — such as those causing type 1 or type 2 VWD — compounds with R924Q additively. In the Hickson cohort, 5 of 6 R924Q-carrying VWD cases had an additional VWF mutation, suggesting R924Q functions as a disease modifier that amplifies the effect of a primary mutation rather than a standalone cause.