rs28647808 — ADAMTS13 Pro618Ala

Missense variant in the spacer domain of ADAMTS13 that reduces VWF-cleaving protease activity and, in type 2 diabetics, increases renal and cardiovascular complication risk with preferential benefit from ACE inhibitor therapy

See your personal result for ADAMTS13

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

ADAMTS13 Pro618Ala — When Blood Clot Regulation Meets Diabetic Kidneys

Your blood contains a molecular scissors called ADAMTS1311 ADAMTS13
A Disintegrin and Metalloproteinase with Thrombospondin motifs 13, a protease whose sole critical job is to cut ultra-large von Willebrand factor (VWF) multimers into smaller, manageable pieces. Without this cleavage, VWF multimers accumulate in circulation and on vessel walls, triggering spontaneous platelet aggregation that can cause dangerous microvascular blockages. The rs28647808 variant in the ADAMTS13 spacer domain substitutes proline for alanine at position 618, reducing how efficiently the enzyme is secreted and how actively it cleaves VWF — with consequences that become clinically significant when kidneys are already under metabolic stress from type 2 diabetes.

The Mechanism

The spacer domain of ADAMTS13 (residues 556–685) is essential both for recognizing and binding VWF and for maintaining proper protein folding and secretion. Position 618 sits within the β6–β7 loop of this domain, adjacent to an N-linked glycosylation site at residue 614 that is important for protein stability. The Pro618→Ala substitution replaces a medium-size hydrophobic residue (proline) with a small hydrophobic residue (alanine), altering the loop's geometry and reducing both protease secretion and VWF-cleaving activity — as confirmed in cell-expression studies where the Ala618 protein showed measurably lower proteolytic output than the wild-type Pro618 protein.

The result is a partial, inherited reduction in ADAMTS13 function. This has limited consequences in healthy vasculature, where only modest ADAMTS13 activity is needed to keep VWF multimers in check. But in type 2 diabetes — where chronic hyperglycemia damages endothelial cells, increases VWF release, and promotes a hypercoagulable milieu — even a partial reduction in ADAMTS13 function can tip the balance toward intra-capillary thrombosis. The renal microvasculature, with its high surface area and filtration demands, is especially vulnerable to this mechanism.

The Evidence

The central evidence comes from the BENEDICT trial22 BENEDICT trial
BErgamo NEphrologic DIabetes Complications Trial Phase A — a randomized controlled trial of 1,163 normoalbuminuric type 2 diabetic patients genotyped for Pro618Ala and randomized to ACE inhibitor (trandolapril) or non-ACEi therapy. Ala carriers (about 17% of patients, matching Hardy-Weinberg expectations for an ~8.8% G allele frequency in Europeans) had dramatically different outcomes depending on treatment:

  • Ala carriers without ACEi: HR 8.50 (95% CI 2.42–29.96) for new-onset microalbuminuria (renal events) relative to Ala carriers on ACEi
  • Ala carriers with ACEi: completely protected — outcomes indistinguishable from the low-risk reference group
  • Pro/Pro homozygotes without ACEi: HR 4.77 (95% CI 1.48–15.36) — elevated but well below the Ala carrier risk
  • Interaction p-value: 0.019 for renal events; 0.014 for combined renal/cardiovascular events

A substudy of 487 patients33 substudy of 487 patients
Rurali et al., Diabetes 2013 confirmed the mechanistic link: Ala carriers had significantly lower serum ADAMTS13 activity than Pro/Pro homozygotes, and ADAMTS13 activity was inversely correlated with renal events (r = −0.326, p = 0.027), cardiovascular events (r = −0.351, p = 0.026), and combined events (r = −0.288, p = 0.009). Among Ala carriers, ACEi therapy significantly raised ADAMTS13 activity — no such effect was seen in Pro/Pro homozygotes — suggesting that ACEi may enhance ADAMTS13 bioavailability by reducing the competition between ADAMTS13 and the hypercoagulable environment induced by angiotensin-II signaling.

A smaller cross-sectional study of 86 type 2 diabetics44 smaller cross-sectional study of 86 type 2 diabetics
Taniguchi et al., Thromb Res 2010 found significantly lower ADAMTS13 antigen levels in patients with overt nephropathy versus normoalbuminuric patients, and a positive correlation between the VWF/ADAMTS13 ratio and carotid intima-media thickness — reinforcing the link between impaired VWF proteolysis and vascular damage in diabetic disease.

Mendelian randomization analyses55 Mendelian randomization analyses
Ye and Zheng, Front Genetics 2021 using large GWAS datasets (5,448 individuals for ADAMTS13 activity; up to 337,000 for cardiovascular outcomes) found that lower ADAMTS13 activity — not merely lower protein levels — is causally associated with higher risks of coronary heart disease (β = −0.0041, p = 0.037) and myocardial infarction (β = −0.0048, p = 0.027), providing genetic-causal support for the protein's role across the cardiovascular spectrum.

Importantly, a study in chronic coronary disease patients without diabetes (MASS II trial, n=56066 MASS II trial, n=560
PMID 19427680) found no independent association between Pro618Ala and cardiovascular events, suggesting the variant's risk may be specifically expressed in the context of diabetic vascular injury rather than being a universal cardiovascular risk factor.

Practical Actions

For the roughly 83% of people who carry two wild-type Pro618 alleles, ADAMTS13 function is at its highest genetically-determined level, and no specific action is needed beyond standard cardiovascular care.

For Ala carriers — especially those with type 2 diabetes — the evidence from BENEDICT has a clear clinical implication: ACE inhibitors appear to provide genotype-specific protection that goes beyond their standard reno- and cardioprotective effects. If you carry the Ala allele and have diabetes, early and consistent ACEi therapy may be particularly important for preserving kidney function. This doesn't override other considerations (allergies, cough, potassium levels, kidney function), but it adds a pharmacogenomic argument for ACEi preference over other antihypertensive classes when clinical choice exists.

Monitoring ADAMTS13 activity directly (via functional plasma assay) is technically possible but not standard clinical practice. Monitoring renal function closely — microalbuminuria screening annually — gives a practical early-warning window for the intrarenal thrombosis that the mechanism predicts.

Interactions

The ADAMTS13 Pro618Ala effect is strongly modulated by metabolic context: the variant shows its most pronounced phenotype in type 2 diabetes, where hyperglycemia amplifies VWF release from endothelial cells and creates the substrate overload that reduced ADAMTS13 activity cannot handle. Outside of diabetic vascular disease, the variant appears clinically silent for cardiovascular endpoints.

Von Willebrand factor level-raising variants (e.g., ABO blood group locus SNPs that affect VWF clearance, or VWF gene variants) represent a plausible interaction class — elevated VWF combined with reduced ADAMTS13-mediated cleavage would compound the prothrombotic burden — though direct genotype × genotype evidence for Pro618Ala plus VWF variants has not been formally studied.

Drug Interactions

trandolapril increased_efficacy literature
ramipril increased_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Full Protease Activity Normal

Normal ADAMTS13 VWF-cleavage activity

You carry two copies of the common Pro618 allele (CC genotype), meaning your ADAMTS13 spacer domain is structurally intact at position 618. Your protease secretion and VWF-cleaving activity are at the highest level determined by this variant. About 84% of people of European ancestry share this genotype. In the BENEDICT trial, Pro/Pro homozygotes had the lowest baseline risk for diabetic renal complications among the three genotype groups.

CG Reduced Protease Activity Intermediate

One copy of the Ala618 allele — reduced ADAMTS13 activity

The mechanism involves impaired proteolysis of ultra-large von Willebrand factor (VWF) multimers in the renal microvasculature. Under normal metabolic conditions, one functional ADAMTS13 allele is sufficient to maintain adequate VWF cleavage. Under diabetic stress — where endothelial VWF secretion is amplified by hyperglycemia and oxidative injury — the reduced proteolytic reserve becomes functionally significant, allowing prothrombotic VWF multimers to accumulate in renal capillaries. The ACEi-specific benefit may reflect angiotensin-II's role in promoting endothelial stress and VWF release: by blocking this pathway, ACEi therapy reduces the VWF substrate burden that overwhelms the impaired ADAMTS13 enzyme.

GG Lowest Protease Activity Reduced

Two copies of the Ala618 allele — substantially reduced ADAMTS13 activity

As a GG homozygote, you have no Pro618 ADAMTS13 protein at all — only the less-efficient Ala618 isoform. In vitro expression studies confirmed that the Ala618 protein secretes less efficiently and has lower proteolytic activity than the Pro618 form. Outside of type 2 diabetes, this variant is classified as likely benign (ClinVar/UniProt), as the reduction in activity is partial and compatible with normal hemostasis. However, in the presence of diabetic vascular stress, the activity reduction becomes clinically meaningful. ADAMTS13 deficiency (as distinct from this variant, which is mild — not a TTP-causing mutation) is causally linked to increased coronary heart disease and myocardial infarction risk by Mendelian randomization, providing additional rationale for protecting residual enzyme function through ACEi therapy.