Prothrombin clotting variant

Prothrombin is a blood-clotting protein. A common clotting variant raises how much prothrombin you make, modestly increasing the risk of vein clots.

What the prothrombin variant does

Prothrombin is the precursor of thrombin, the enzyme that converts fibrinogen into the fibrin mesh of a clot. This variant, known as G20210A, sits in the untranslated tail of the gene rather than in its coding sequence, and it makes the messenger RNA more stable, so more prothrombin is produced.

Carriers typically run prothrombin levels around 30% higher than average. Nothing about the protein is abnormal, there is simply more of it, which tilts the balance toward clotting.

How strong the evidence is

The catalogued association draws on the same very large study as Factor V Leiden, more than 1.5 million people, with a p-value below 1e-170 and an odds ratio near 2 per copy for venous thromboembolism. ClinVar records it under venous thromboembolism, ischaemic stroke and recurrent pregnancy loss.

That places it as the second most common inherited clotting tendency in people of European ancestry, with an effect roughly half to two thirds that of Factor V Leiden.

How common it is, and what it means in absolute terms

In 1000 Genomes reference data, about 2.5% of European-ancestry individuals carry one copy and two copies are rare, at roughly 1 in 6,000. It is close to absent in East Asian samples and uncommon in African-ancestry ones.

Against a background risk of roughly 1 to 2 venous clots per 1,000 people per year, doubling that leaves the absolute risk low for most carriers. As with Factor V Leiden, the variant matters mainly where it meets a trigger: surgery, immobility, pregnancy and the postpartum weeks, oestrogen-containing contraception or hormone therapy, cancer and serious infection.

Carrying both variants

Prothrombin G20210A and Factor V Leiden are each read separately on this site, and some people of European ancestry carry both. That combination raises risk more than either alone and is one of the situations where clinical literature reports substantially higher pregnancy-associated risk, in the range of 1 in 20 to 1 in 100 pregnancies for homozygous or combined thrombophilias.

If you carry both, that is worth mentioning to a clinician before surgery, pregnancy planning or starting oestrogen-containing contraception, rather than something to act on independently.

What this variant does not tell you

The rarer, stronger inherited causes of clotting, deficiencies of antithrombin, protein C and protein S, are diagnosed by blood testing rather than by a genotyping chip, and antiphospholipid syndrome is acquired. A negative result here rules none of them out.

Guidelines do not recommend thrombophilia screening in asymptomatic people, because a positive result seldom changes management on its own. Its value is as context in the specific situations above.

What each rs1799963 genotype means

rs1799963 has three possible genotypes: GG, AG and AA.

No prothrombin variant (rs1799963 GG). You don't carry the common clotting variant that raises prothrombin, so from what this gene shows your blood-clotting protein levels are typical and your clot risk is at baseline.

Higher clot risk (rs1799963 AG). You carry one copy of the common clotting variant that raises prothrombin (a blood-clotting protein) a little, which modestly increases the risk of vein clots. Most carriers never have a clot, but it's worth knowing around surgery, long travel, pregnancy or estrogen-containing birth control.

High clot risk (rs1799963 AA). You have two copies of the clotting variant that raises prothrombin (uncommon), which raises your clotting protein more and increases the risk of vein clots. This is worth discussing with a doctor, especially around surgery, pregnancy or hormone use, where simple precautions help.

Evidence & sources

Across global populations, fewer than 1% of people carry two copies of this variant, and about 98% carry none.

This variant appears in 10 published genetic studies: PubMed 25772935 · PubMed 26908601 · PubMed 28373160 · PubMed 31420334 · PubMed 31676865 · PubMed 35285134 · PubMed 36154123 · PubMed 36777996 · PubMed 39024449 · PubMed 39789286.

Common questions

How much does prothrombin G20210A raise clot risk? About twofold per copy in very large studies, roughly half to two thirds the effect of Factor V Leiden. Against a baseline of 1 to 2 clots per 1,000 people per year, that leaves absolute risk low outside of trigger situations.

Is this the same as having thick blood? No. Carriers have somewhat more prothrombin protein circulating, not thicker blood, and standard blood counts look normal. The tendency shows up as a raised chance of a venous clot, particularly around surgery, immobility, pregnancy or oestrogen use.

Related

Atrial fibrillation · Autoimmune risk (PTPN22 R620W) · Colorectal cancer risk (8q24) · Longevity-associated variant (FOXO3) · Prostate cancer (male) · Type 2 diabetes risk · Venous thromboembolism (clots)