rs33978901 — VWF p.Arg924Gln

VWF missense variant (R924Q) that reduces von Willebrand factor and Factor VIII levels, particularly in blood group O carriers, increasing bleeding risk when combined with other VWF variants or low-VWF states

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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.

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-carrier Normal

Common VWF genotype — no R924Q-associated reduction in VWF or Factor VIII

You carry two copies of the common C allele at rs33978901, meaning your VWF gene does not carry the R924Q variant. This is the most prevalent genotype, present in approximately 96% of people of European descent and over 99% of those of African or East Asian ancestry. Your VWF and Factor VIII production are unaffected by this locus.

CT R924Q Carrier Carrier

One copy of R924Q — reduced VWF and Factor VIII, especially with blood group O

The R924Q variant does not appear to produce a structurally abnormal VWF protein in cell culture; recombinant studies showed normal secretion, multimer formation, and FVIII binding. Instead, the allele travels on a chromosomal haplotype associated with lower VWF output. In the landmark Hickson et al. study (1,115 controls, 148 VWD index cases), 35 heterozygous carriers were identified in healthy controls, and the variant explained ~10% of VWF/FVIII variance overall — jumping to 35% in blood group O co-carriers.

ClinVar classifies R924Q as benign or uncertain significance in isolation. Its clinical importance scales with context: normal blood group + no other VWF variants = minimal risk; blood group O + low-normal VWF baseline = worth testing; blood group O + additional VWF pathogenic variant = VWD disease-modifier territory.

In 5 of 6 VWD index cases carrying R924Q, a second VWF mutation was present, confirming its role as an amplifier rather than a primary cause.

TT R924Q Homozygous Homozygous

Two copies of R924Q — substantially reduced VWF and Factor VIII requiring clinical assessment

Homozygous R924Q has not been reported as a standalone VWD diagnosis in the published literature — the Hickson et al. cohort identified only one homozygous individual among 1,115 controls, with no clinical VWD phenotype recorded. However, the additive effect of two variant haplotypes on VWF production would be expected to reduce levels substantially below the heterozygous range, and in blood group O individuals this could reach clinically significant thresholds.

Given the rarity of this genotype, clinical management should be guided by measured VWF and FVIII levels rather than assumed from genotype alone. A full hemostasis evaluation by a hematologist experienced in bleeding disorders will establish your functional phenotype and guide any necessary intervention.