rs369504169 — PROC p.Arg42His (c.125G>A)

Rare missense variant in the PROC gene encoding protein C; the A allele substitutes histidine for arginine at position 42, partially impairing anticoagulant function and increasing venous thromboembolism risk 3-7 fold in heterozygous carriers

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PROC Arg42His — Protein C Deficiency and Inherited Thrombophilia

Protein C is the body's front-line anticoagulant brake. Released into circulation as an inactive precursor, it is activated when thrombin binds thrombomodulin11 thrombomodulin
a receptor on endothelial cells lining blood vessels that converts thrombin from a procoagulant to an anticoagulant enzyme on the vessel wall. Activated protein C (APC) then cleaves and inactivates coagulation factors Va and VIIIa22 factors Va and VIIIa
both are essential amplifiers of the coagulation cascade; Va is a cofactor for prothrombinase, and VIIIa is a cofactor for the tenase complex — inactivating them shuts down clot propagation, dramatically slowing clot propagation. Without adequate protein C, coagulation continues unchecked after the initial trigger, raising the probability of pathological thrombosis.

The rs369504169 A allele introduces a c.125G>A substitution33 c.125G>A substitution
nucleotide 125 of the coding sequence; G is the GRCh38 plus-strand reference base at chr2:127,421,337 in exon 3 of PROC, replacing the arginine at position 42 with histidine (p.Arg42His). ClinVar classifies this variant as likely pathogenic, with submissions documenting affected individuals with autosomal dominant thrombophilia and documented deep venous thrombosis. The variant is extremely rare globally — the A allele is present at approximately 0.001% frequency or less across all gnomAD populations.

The Mechanism

Arginine 42 lies within the Gla domain44 Gla domain
a vitamin K-dependent gamma-carboxyglutamic acid (Gla) domain at the N-terminus of protein C; this domain binds calcium and anchors the protein to phospholipid membranes on endothelial surfaces, positioning it to interact with thrombomodulin and to be activated by the thrombin-thrombomodulin complex of the protein C precursor. Substituting positively charged arginine with histidine alters the local charge environment of this domain, which is thought to impair proper membrane anchoring or receptor interaction. Studies of closely related arginine residues in the Gla domain have confirmed that charge changes at these positions reduce protein C functional activity — the p.Arg42His variant has been noted to produce discrepant results between amidolytic (chromogenic substrate) assays and clotting-based functional assays, which is a hallmark of Type II protein C deficiency55 Type II protein C deficiency
normal antigen level but reduced functional activity; contrasts with Type I where both antigen and activity are reduced proportionally.

Heterozygous carriers produce one functional and one impaired protein C allele, resulting in approximately 50-65% of normal protein C activity — below the 70 IU/dL threshold typically considered normal. This partial deficiency is sufficient to elevate venous clotting risk without causing the catastrophic thrombosis seen in homozygotes (who typically have protein C activity below 1%).

The Evidence

A meta-analysis of 107,130 individuals across 107 publications66 meta-analysis of 107,130 individuals across 107 publications
Alnor et al., Annals of Hematology, 2024; 21,560 VTE events analysed found that protein C deficiency carries an odds ratio of 3.23 (95% CI 2.05-5.08) for a first venous thromboembolism. Earlier prospective data from a cohort study tracking relatives of protein S, protein C, and antithrombin deficiency probands found an annual VTE incidence of 1.53%77 annual VTE incidence of 1.53%
compared to 0.29% in unaffected relatives; adjusted hazard ratio 7.0 (95% CI 2.7-18.0) in affected individuals — a 7-fold increase.

The specific p.Arg42His (c.125G>A) variant was identified as novel in a 2025 case report of neonatal purpura fulminans88 2025 case report of neonatal purpura fulminans
Francis et al., Indian Journal of Dermatology, 2025, where a homozygous infant presented with disseminated intravascular coagulation and vitreous haemorrhage — consistent with the near-complete absence of protein C in biallelic carriers. In heterozygous form, p.Arg42His has been documented in patients with deep venous thrombosis and thromboembolism99 patients with deep venous thrombosis and thromboembolism
NIHR ThromboGenomics study, n=2,396 patients sequenced; rs369504169 identified as likely pathogenic by ACMG criteria by the NIHR ThromboGenomics consortium.

The 2023 American Society of Hematology guidelines on thrombophilia testing1010 2023 American Society of Hematology guidelines on thrombophilia testing
Middeldorp et al., Blood Advances 2023; PMID 37195076; the most current evidence-based guidance conditionally recommend testing for protein C deficiency in individuals with a family history of the deficiency when considering thromboprophylaxis for minor provoking risk factors, and specifically to guide avoidance of combined hormonal contraceptives in women.

Practical Actions

Heterozygous carriers are not inevitably destined to develop thrombosis — many live without a clot event — but the elevated baseline risk becomes clinically significant whenever additional thrombophilic triggers are present. The key risks to proactively manage are: combined hormonal contraceptives (estrogen increases coagulation factor synthesis, compounding protein C deficiency risk), high-risk surgical and immobilisation periods, and pregnancy or postpartum (already the highest-risk VTE window in women's lives).

ASH 2023 guidelines support indefinite anticoagulation after a first VTE event in confirmed protein C deficiency carriers, in contrast to the standard 3-6 months recommended for provoked VTE without thrombophilia. This makes knowing carrier status genuinely decision-changing for anticoagulation duration after any thrombotic event.

Interactions

The most clinically significant interaction involves Factor V Leiden (rs6025, F5 R506Q)1111 Factor V Leiden (rs6025, F5 R506Q)
Factor V Leiden prevents APC from inactivating Factor Va — when protein C is already partially deficient, this APC resistance compounds the anticoagulant failure at two independent points in the cascade. Double carriers of protein C deficiency and Factor V Leiden face substantially greater VTE risk than either variant alone. Similarly, [the prothrombin G20210A variant (rs1799963) | raises circulating prothrombin levels 30%, increasing thrombin availability and clot propagation] compounds protein C deficiency by generating more thrombin than a protein C system already running at 50-65% capacity can neutralize. These interactions warrant compound action assessment and should be documented in the medical record alongside this variant.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

No PROC Arg42His variant detected — standard protein C anticoagulant function at this locus

You carry two copies of the reference G allele at rs369504169. Your PROC gene at this position is unaffected by the p.Arg42His mutation, and your protein C anticoagulant function is not impaired by this variant. The G allele is the overwhelming population majority — over 99.99% of people share this genotype. Inherited thrombophilia from this PROC variant is not a concern for you.

Note that protein C deficiency can be caused by many other PROC mutations not covered by this variant — clinical plasma protein C activity testing is the most comprehensive way to assess actual deficiency if suspected.

AG Protein C Deficiency Carrier High Risk

One copy of PROC Arg42His — partial protein C deficiency with 3-7x elevated VTE risk

The p.Arg42His substitution alters a charged residue in the Gla domain of protein C, impairing its membrane anchoring and activation efficiency. This produces a Type II-like protein C deficiency pattern — functional activity is more impaired than antigen level — resulting in reduced capacity to inactivate coagulation factors Va and VIIIa once a clot begins forming.

Key provocation-specific risks for carriers: - Combined hormonal contraceptives: Estrogen-containing pills, patches, and rings increase coagulation factor synthesis and reduce natural anticoagulants, compounding protein C deficiency. This interaction multiplicatively elevates VTE risk; non-estrogen alternatives are strongly preferred. - Pregnancy and postpartum: Pregnancy is already the highest-risk VTE period in women's lives, with risk peaking in the postpartum period. Protein C deficiency adds further to this elevated baseline. Antepartum and postpartum thromboprophylaxis discussions with a hematologist are warranted. - Surgery and immobilisation: Standard surgical thromboprophylaxis applies, but this status should be documented so extended prophylaxis can be considered for high-risk procedures. - After a first VTE: ASH 2023 guidelines support indefinite anticoagulation for protein C deficiency carriers who experience a first VTE — a clinically meaningful departure from the standard 3-6 month treatment for provoked events without thrombophilia.

First-degree relatives (parents, siblings, children) each have a 50% chance of inheriting this variant and should be offered testing, especially before starting hormonal contraceptives or facing other thrombotic triggers.

AA Homozygous (Extremely Rare) Homozygous

Two copies of PROC Arg42His — severe protein C deficiency, high risk of life-threatening neonatal thrombosis

The homozygous state of p.Arg42His has been documented in a neonatal case presenting with purpura fulminans, disseminated intravascular coagulation, and vitreous haemorrhage — the cardinal phenotype of severe congenital protein C deficiency. Protein C activity in biallelic PROC pathogenic variant carriers is typically below 1 IU/dL (normal: 70-140), which is insufficient to prevent runaway coagulation in the neonatal period when procoagulant factors temporarily surge.

Confirmed severe protein C deficiency requires urgent management: - Protein C concentrate (Ceprotin) is the preferred replacement therapy in acute thrombotic crises and for prophylaxis - Fresh frozen plasma (FFP) is an alternative when concentrate is unavailable - Warfarin-based long-term anticoagulation has been used in older patients but carries risk of warfarin-induced skin necrosis if introduced without protein C replacement cover - All estrogen-containing hormonal treatments are absolutely contraindicated

If this result appears in an adult with no prior medical history of neonatal purpura fulminans, there are two possibilities: genotyping error (confirm with clinical-grade sequencing) or a phenotypically mild biallelic state that evaded neonatal presentation. Either scenario requires urgent specialist evaluation.