rs61750630 — VWF C2362F

Pathogenic missense variant in von Willebrand factor causing intracellular retention of the mutant protein; homozygosity causes severe type 3 von Willebrand disease, heterozygous carriers typically have reduced VWF levels and mild bleeding symptoms

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VWF C2362F — A Founder Mutation That Silences the Bleeding Brake

Von Willebrand factor is the molecular glue of hemostasis: a multimeric glycoprotein that captures platelets at the site of a vascular injury and shuttles factor VIII through the bloodstream. Without adequate VWF activity, even minor cuts fail to clot properly and surgical bleeding can become life-threatening. The rs61750630 variant — encoding the C2362F substitution11 C2362F substitution
cysteine-to-phenylalanine change in the D4 domain of VWF — is a pathogenic missense change that disrupts protein folding in the endoplasmic reticulum, preventing most of the mutant protein from ever reaching the bloodstream. It was first identified as a founder mutation in northern Italian families with type 3 von Willebrand disease22 founder mutation in northern Italian families with type 3 von Willebrand disease
autosomal recessive severe VWD with near-absent VWF.

The Mechanism

VWF contains a series of cysteine-rich domains that form disulfide bonds critical for proper multimerization and secretion33 disulfide bonds critical for proper multimerization and secretion
loss of a cysteine removes one bond from an intricate disulfide network. The Cys2362Phe substitution eliminates a cysteine in the D4 domain, disrupting the local disulfide architecture. The misfolded protein is retained in the endoplasmic reticulum rather than trafficked to the Golgi and secreted. Tjernberg et al. showed that cells expressing only VWF-C2362F secrete just 8% of normal VWF antigen levels44 Tjernberg et al. showed that cells expressing only VWF-C2362F secrete just 8% of normal VWF antigen levels
compared to wild-type controls. Crucially, it is the loss of the cysteine itself — not the bulky phenylalanine side chain — that causes retention, since the same group showed the defect is structural rather than steric. When mutant and wild-type constructs are co-expressed (mimicking the heterozygous state), secretion reaches approximately 50% of normal, consistent with the mildly reduced VWF levels observed in carriers.

A further complication emerges upon desmopressin (DDAVP) stimulation: although homozygous patients do release some VWF in response to DDAVP, the mutant protein has a 2-fold shortened plasma half-life55 2-fold shortened plasma half-life
suggesting impaired interactions with ADAMTS13 or stabilizing proteins, making DDAVP a poor treatment option for severely affected patients.

The Evidence

Eikenboom et al. characterised eight northern Italian families with recessive VWD66 Eikenboom et al. characterised eight northern Italian families with recessive VWD
identifying mutations in 14 of 16 disease-associated VWF alleles. The C2362F substitution appeared in every type 3 VWD patient from a subgroup previously noted for an unusually strong factor VIII response to desmopressin — a clinical phenotype that correlates with the founder haplotype. Haplotype analysis supported a single ancestral origin, making this one of the clearest examples of a VWF founder effect in a defined European population.

The inheritance picture is more nuanced than purely recessive. Bowman et al. studied 34 Canadian families with 31 distinct VWD type 3 mutations77 Bowman et al. studied 34 Canadian families with 31 distinct VWD type 3 mutations
including C2362F carriers and found that in approximately half of families, heterozygous parents had bleeding symptoms and reduced VWF levels sufficient to diagnose type 1 VWD — evidence of co-dominant inheritance rather than a purely silent carrier state88 co-dominant inheritance rather than a purely silent carrier state
48% of obligate carriers received a clinical VWD diagnosis. This means the risk_allele does not recede invisibly in the heterozygous state.

Given the global allele frequency of approximately 3.4 per million chromosomes in Europeans (gnomAD v4, n = 1,400,916 exomes), the C2362F variant is extremely rare outside of the northern Italian founder population. Homozygosity is essentially unique to that ancestry.

Practical Actions

For heterozygous carriers, the key step is a formal bleeding assessment: measure VWF antigen, VWF activity (ristocetin cofactor), and factor VIII. Levels around 50% of normal are typical; values below 30 IU/dL meet the diagnostic threshold for type 1 VWD and should trigger referral to a haematologist. Carriers should disclose their genetic status before any surgical procedure, dental extraction, or childbirth so a proactive haemostasis plan can be put in place.

For the rare homozygous individual, management follows type 3 VWD guidelines: plasma-derived or recombinant VWF concentrate (Vonvendi, Wilate, Humate-P) is the mainstay of treatment. DDAVP is not effective in type 3 VWD — VWF stores are severely depleted and the small amount released is cleared too rapidly to provide sustained haemostasis. All family members should be offered VWF screening.

Interactions

Carriers of two VWF null alleles (different mutations in trans, i.e. compound heterozygotes) present identically to homozygotes clinically. ABO blood group independently modulates VWF antigen levels — blood group O reduces VWF by approximately 25%, which can compound the haemostatic deficit in carriers who also have blood group O. Concurrent thrombocytopenia or platelet function defects (e.g. variants in GP1BA encoding the VWF receptor, or TBXA2R affecting platelet activation) can further worsen bleeding in VWF-deficient individuals.

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-carrier Normal

No VWF C2362F variant detected — typical von Willebrand factor function expected

You carry two copies of the common C allele at rs61750630, meaning you do not carry the VWF C2362F pathogenic variant. This variant is extremely rare globally (about 3.4 per million chromosomes in Europeans, with near-zero frequency in other ancestries). Your von Willebrand factor function is not affected by this specific variant. If you or family members have a personal or family history of abnormal bleeding, other VWF variants or bleeding disorders should be evaluated separately.

AC Carrier Carrier

One copy of the pathogenic C2362F variant — heterozygous carrier with typically reduced VWF levels

The C2362F mutation reduces VWF secretion in heterozygous carriers to approximately 50% of normal, as demonstrated by Tjernberg et al.'s co-transfection experiments showing ~50% antigen when mutant and wild-type constructs are expressed together — directly mirroring the in vivo carrier state. While classical teaching describes VWD type 3 as autosomal recessive, Bowman et al. showed in 34 Canadian VWD families that inheritance is co-dominant in roughly half of families: carriers have measurable bleeding symptoms and reduced VWF sufficient to diagnose type 1 VWD. Bleeding episodes tend to be mucosal — heavy menstrual periods, nosebleeds, prolonged bleeding from cuts — rather than the deep joint bleeds seen in haemophilia. VWF levels can also be lowered by blood group O (which reduces VWF by ~25%), stress, thyroid disease, and pregnancy (when VWF normally rises substantially to compensate). Before surgical procedures, carriers should have VWF antigen and activity measured and a haemostatic plan prepared.

AA Homozygous — Type 3 VWD Homozygous

Two copies of the pathogenic C2362F variant — consistent with severe type 3 von Willebrand disease

Tjernberg et al. demonstrated that cells expressing homozygous VWF-C2362F secrete only 8% of normal VWF antigen into culture medium, with the remainder retained intracellularly in the endoplasmic reticulum due to misfolding caused by loss of the Cys2362 disulfide bond. Clinically, homozygous type 3 VWD patients have VWF antigen and activity levels typically below 1–3 IU/dL, making them functionally VWF-deficient. Factor VIII co-circulates bound to VWF; without VWF to stabilize it, FVIII is also markedly reduced, creating a combined deficiency resembling moderate haemophilia A in its impact on the intrinsic coagulation pathway. The C2362F founder haplotype was identified specifically in northern Italian families and is rare outside this population.

DDAVP infusion does cause a 2-fold increase in plasma VWF-C2362F but the abnormal protein is cleared from circulation twice as fast as normal VWF, providing inadequate haemostatic coverage. Management therefore relies on exogenous VWF replacement: plasma-derived concentrates (Wilate, Humate-P, Alphanate) or recombinant VWF (Vonvendi/vonicog alfa) that supply the full range of high-molecular-weight multimers essential for primary haemostasis. Long-term prophylaxis (infusions two to three times weekly) is recommended for patients with frequent joint or soft-tissue bleeding.