rs61750581 — VWF S1613P

VWF S1613P — A2 Domain Instability and the Loss of Platelet-Capture Multimers

Von Willebrand factor is not a single molecule but a polymer — its biological power comes from assembling into enormous high-molecular-weight multimers¹¹ high-molecular-weight multimers
Ultra-large VWF strings secreted by endothelial cells after injury; these structures are the only form capable of capturing platelets under high arterial shear conditions; loss of these multimers is the defining feature of type 2A von Willebrand disease that can deploy across a damaged vessel wall and capture flowing platelets within microseconds. The A2 domain of VWF contains the cleavage site for ADAMTS13²² ADAMTS13
A disintegrin and metalloproteinase with thrombospondin motifs 13; a circulating metalloprotease that trims VWF multimers to normal size under shear; overactivity or hypersusceptibility causes loss of the largest, most hemostatically active multimers — a protease that regulates multimer size by cutting the chain. The A2 domain is normally kept tightly folded, burying the ADAMTS13 cleavage site and protecting the multimer from premature destruction. The rs61750581 S1613P substitution — a serine-to-proline change at position 1613 — replaces a flexible amino acid with proline, which kinks the local backbone and destabilizes the A2 domain fold. The result is a VWF multimer that is proteolyzed too readily, depleting the high-molecular-weight forms needed for normal hemostasis.

This variant is listed as OMIM allelic variant 613160.0009 for von Willebrand disease type 2A. As of February 2025, the ClinGen von Willebrand Disease Variant Curation Expert Panel reclassified it from pathogenic to Uncertain Significance (VUS), based on emerging criteria for VWD-specific variant interpretation. It meets PP3 (computational evidence of pathogenicity), PS4_Supporting (case enrichment), and PP4_Moderate (phenotype specificity), but does not yet have sufficient independent evidence to satisfy full pathogenicity criteria under current VWD curation rules.

The Mechanism

The VWF A2 domain normally adopts a β-propeller-like fold³³ β-propeller-like fold
A compact secondary structure with hydrophobic core that buries the ADAMTS13 binding region and scissile bond; disruption of this fold is the shared mechanism of all classical type 2A VWD group II mutations that shields the ADAMTS13 cleavage site Tyr1605–Met1606 from protease access. Under arterial shear, unfolding is regulated and transient — but type 2A A2 domain mutations constitutively destabilize this fold even at rest.

A FRET-based assay separating the N- and C-termini of the A2 domain demonstrated that 7 of 8 type 2A mutations tested caused persistent separation of the domain's termini⁴⁴ 7 of 8 type 2A mutations tested caused persistent separation of the domain's termini
Lynch et al., PLoS One 2017 — mutations that separate N- and C-termini promote an open conformation that exposes ADAMTS13 binding and scissile bond sites constitutively, producing a constitutively open conformation that exposes the ADAMTS13 binding and scissile sites. Earlier work confirmed that 11 of 13 A2 domain VWD type 2A mutations increased specific ADAMTS13 proteolysis⁵⁵ 11 of 13 A2 domain VWD type 2A mutations increased specific ADAMTS13 proteolysis
Hassenpflug et al., Blood 2006 — ADAMTS13 susceptibility correlated directly with in vivo multimer loss seen in patient plasma, and that the degree of proteolytic susceptibility correlated directly with the degree of HMWM loss observed in patient plasma.

An in vivo rat model demonstrated that VWF carrying the S1613P mutation undergoes accelerated proteolysis in vivo resulting in loss of high-molecular-weight multimers⁶⁶ accelerated proteolysis in vivo resulting in loss of high-molecular-weight multimers
Stoddart et al., Blood 1996 — the only published experimental evidence specifically characterizing S1613P in a living model; shows the mutation recapitulates the type 2A phenotype with appearance of satellite proteolytic fragments, while overall VWF clearance rates remain comparable to normal protein, meaning the functional deficit is selective: only the large, hemostatically active multimers are lost.

The Evidence

The variant was originally documented as a pathogenic VWD type 2A cause in OMIM based on early molecular characterization and family studies. A recent Thai multicenter study⁷⁷ Thai multicenter study
Lauhasurayotin et al., J Clin Pathol 2024 — 15 patients with type 2 or type 3 VWD genotyped by whole exome sequencing; p.Ser1613Pro identified among previously described mutations using whole exome sequencing identified p.Ser1613Pro among known pathogenic VWF mutations in VWD patients, confirming its presence in affected individuals across populations.

The February 2025 ClinGen reclassification to VUS reflects the evolution of variant interpretation criteria for VWD, not evidence of benignity. The variant has no functional counterevidence — all experimental data support pathogenicity — but specific evidence thresholds under the formal VWD curation rules are not yet fully met. Clinicians encountering this variant in the context of a confirmed bleeding phenotype should treat it as a strong candidate for clinical significance pending future reclassification.

Type 2A VWD — the disease associated with this variant — manifests as mucocutaneous bleeding including epistaxis, easy bruising, heavy menstrual bleeding, and post-surgical hemorrhage⁸⁸ mucocutaneous bleeding including epistaxis, easy bruising, heavy menstrual bleeding, and post-surgical hemorrhage
Seidizadeh et al., Semin Thromb Hemost 2026 — comprehensive clinical update on type 2A VWD. Laboratory hallmarks include a reduced VWF:RCo/VWF:Ag ratio (platelet-binding activity disproportionately lower than antigen level), reduced VWF:CB/VWF:Ag ratio, and selective loss of high- and intermediate-molecular-weight multimers on gel electrophoresis.

Practical Implications

Anyone carrying a G allele at rs61750581 with a personal or family history of unusual bleeding should pursue hematology evaluation. Diagnostic workup should include VWF antigen, VWF ristocetin cofactor activity, VWF collagen binding, FVIII:C, and VWF multimer analysis — the full type 2A laboratory panel. A DDAVP (desmopressin) responsiveness test is appropriate before any procedure, as type 2A heterozygotes can show a transient but often insufficient response⁹⁹ type 2A heterozygotes can show a transient but often insufficient response
Michiels & van Vliet, Acta Haematol 2009 — complete response in mild type 2A lasts only hours; inadequate for surgical prophylaxis in most patients. VWF concentrates containing both VWF and FVIII (Humate-P, Wilate, Vonvendi) are the standard treatment for major bleeding events and surgical prophylaxis.

Women with this variant are at particular risk for heavy menstrual bleeding, which often precedes formal VWD diagnosis by years and significantly impacts quality of life. Menorrhagia in VWD carriers is managed with tranexamic acid, hormonal therapies, or VWF concentrates for severe episodes.

Interactions

VWF S1613P interacts with the general VWF expression level: individuals with an additional low-VWF variant in the other allele may have more pronounced bleeding phenotypes than those with a single functional copy of normal VWF. Blood group O is a well-established environmental modifier — O type individuals have 25–35% lower plasma VWF levels than non-O individuals, which can worsen bleeding phenotype in anyone with a heterozygous VWF functional variant. Blood group O status should be noted when evaluating type 2A carriers clinically.