rs61750584 — VWF I1628T

Missense variant in the VWF A2 domain that destabilizes the protein and increases ADAMTS13 cleavage, causing loss of high-molecular-weight multimers and von Willebrand disease type 2A with mucocutaneous bleeding

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The Cleavage Trap — How a Single Amino Acid Change Dismantles Your Clotting Glue

Von Willebrand factor is the body's primary molecular glue at sites of vascular injury. Synthesized by endothelial cells and platelets, VWF11 VWF
von Willebrand factor — a large glycoprotein that bridges damaged blood vessel walls and circulating platelets to form an initial platelet plug normally circulates as giant multimeric strings. The largest of these high-molecular-weight (HMW) multimers are the most adhesive: they are best at capturing platelets under the shear stress of fast-flowing blood. rs61750584 (G allele) introduces a single amino acid change — isoleucine to threonine at position 1628 (I1628T) — that makes the VWF protein physically fragile at exactly the point where it needs to be strong. The result is von Willebrand disease type 2A, the most common type 2 bleeding disorder, characterized by loss of HMW multimers and a lifelong tendency toward mucocutaneous bleeding.

The Mechanism

The VWF protein contains a central A2 domain22 A2 domain
a compact globular domain flanked by disulfide bonds that conceals the ADAMTS13 cleavage site under physiological conditions. Normally, this domain unfolds only when VWF experiences tensile forces at sites of vascular injury — exposing the Tyr1605–Met1606 bond to proteolysis by ADAMTS1333 ADAMTS13
a metalloprotease that trims excessively large VWF multimers and prevents pathological platelet clumping. The I1628T substitution sits in a hydrophobic core of the A2 domain. The threonine residue is more polar and bulkier than the native isoleucine, disrupting the network of contacts that hold the domain folded.

Molecular dynamics simulations44 Molecular dynamics simulations
computational models applying tensile force to the protein chain and measuring domain stability show that I1628T lowers the tensile force needed to separate the terminal helix α6 from the A2 domain body — the first step in unfolding. Experimental studies confirm that this destabilization translates directly to enhanced ADAMTS13 cleavage: Hassenpflug et al.55 Hassenpflug et al.
Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis. Blood 2006;107:2339-45 showed that I1628T increases susceptibility to ADAMTS13 proteolysis under non-denaturing (physiological) conditions, with the in vitro proteolytic pattern closely paralleling the multimer defect seen in affected patients. The consequence is that HMW VWF multimers are cleaved away continuously in the circulation, leaving only small, less-adhesive forms.

The Evidence

ClinVar classifies this variant as Pathogenic for von Willebrand disease type 2A with a 4-star expert panel review (ClinGen VWD Variant Curation Expert Panel, FDA-recognized, last evaluated August 2024). The evidence package meeting this classification includes: at least 16 documented patients with VWD type 2A carrying this variant, segregation with disease across three generations in the original kindred, laboratory confirmation of very low VWF ristocetin cofactor activity and absent HMW multimers in affected carriers, and consistent computational predictions (REVEL score 0.703).

The variant is absent from gnomAD across all major ancestry groups (fewer than 2 alleles observed in 1.4 million chromosomes), consistent with a highly penetrant pathogenic variant under purifying selection pressure. Unlike the common VWD type 1 variants, which typically reduce VWF quantity without structural abnormality, the I1628T mutation causes a qualitative defect: the protein is produced normally but lacks functional HMW multimers.

A landmark functional study by Hassenpflug et al. (2006)66 A landmark functional study by Hassenpflug et al. (2006)
examining 13 A2 domain mutations and their ADAMTS13 susceptibility established that nearly all type 2A mutations in the A2 region share this property of enhanced proteolysis, and that the degree of proteolysis in the laboratory predicts the clinical bleeding phenotype. A subsequent structural dynamics study by Interlandi et al. (2012)77 structural dynamics study by Interlandi et al. (2012)
PLoS One simulation study of I1628T, L1657I and E1638K confirmed the molecular basis: the threonine substitution reduces the energy barrier for A2 unfolding and is sufficient to render the normally cryptic cleavage site constitutively accessible.

Practical Actions

Carriers of the G allele have pathogenic type 2A VWD inherited in an autosomal dominant pattern — one copy is sufficient to cause disease. Clinical management focuses on three areas: diagnosing the subtype correctly, preparing for bleeding challenges (surgery, trauma, dental procedures), and monitoring for heavy menstrual bleeding.

Laboratory testing should include VWF antigen level, VWF ristocetin cofactor activity (VWF:RCo), VWF:RCo/VWF:Ag ratio (typically less than 0.6 in type 2A), and multimer analysis to confirm the HMW multimer defect. Because type 2A is caused by structural abnormality rather than quantity deficiency, desmopressin (DDAVP)88 desmopressin (DDAVP)
which releases VWF from endothelial storage sites but cannot correct the structural defect is generally ineffective or only transiently helpful in type 2A disease. VWF concentrate replacement therapy (plasma-derived or recombinant VWF) is the preferred treatment during bleeding episodes and peri-operative cover.

Interactions

The mucocutaneous bleeding phenotype of VWD type 2A can be compounded by concurrent use of platelet-function inhibitors (aspirin, NSAIDs, clopidogrel), which impair the platelet side of haemostasis that VWF already bridges less effectively. Any prescription involving antiplatelet or anticoagulant drugs requires explicit discussion with a haematologist aware of the VWD diagnosis.

Inherited thrombocytopenia variants (affecting platelet number) could theoretically worsen the bleeding phenotype additively, though published compound heterozygosity data for this specific combination are limited. Factor VIII levels should be checked at baseline, as VWF normally stabilizes FVIII in the circulation; in type 2A, FVIII may be modestly reduced.

Genotype Interpretations

What each possible genotype means for this variant.

AA Non-carrier Normal

No VWF I1628T variant — standard von Willebrand factor function

You carry the common reference allele at rs61750584. Your VWF A2 domain retains the native isoleucine-1628 residue, maintaining normal structural stability. High-molecular-weight VWF multimers form and persist in your circulation as expected, supporting normal platelet adhesion and primary haemostasis. This genotype accounts for essentially all of the general population.

AG VWD Type 2A Carrier Carrier

One copy of pathogenic I1628T — von Willebrand disease type 2A

The A2 domain destabilization caused by I1628T allows ADAMTS13 to cleave VWF under normal (non-stress) conditions in the circulation, continuously trimming away the largest, most platelet-adhesive multimers. Laboratory testing in carriers typically shows:

  • VWF antigen: low-normal or modestly reduced
  • VWF ristocetin cofactor activity (VWF:RCo): disproportionately reduced relative to antigen
  • VWF:RCo/VWF:Ag ratio: typically below 0.6
  • Multimer analysis: absent or severely reduced high-molecular-weight bands

Desmopressin (DDAVP) is generally ineffective in type 2A disease because it releases more of the structurally abnormal VWF from endothelial stores, not normal protein. VWF concentrate is the standard treatment for acute bleeding episodes and surgical prophylaxis.

Inheritance is autosomal dominant — each child of a carrier has a 50% chance of inheriting the variant.

GG Homozygous VWD 2A Homozygous

Two copies of pathogenic I1628T — severe von Willebrand disease type 2A

While type 2A is dominantly inherited — meaning one copy causes disease — individuals homozygous for a pathogenic VWF A2 domain variant theoretically produce only structurally defective VWF protein from both alleles. No normally-folded protein is available to compensate. Both the endothelial Weibel-Palade body pool and the circulating pool would consist entirely of the less-stable I1628T form. This is expected to result in more severe HMW multimer depletion and more pronounced bleeding than heterozygous disease.

Because GG homozygosity has not been specifically reported in published case series (all documented cases involve heterozygotes), the precise clinical phenotype remains incompletely characterized. The severity assessment below is based on first-principles reasoning from the molecular mechanism and by analogy with homozygosity for other dominant VWD type 2A variants.