rs6063 — FGG Gly191Arg

Rare missense variant in the fibrinogen gamma chain producing a substantially elevated risk of venous thromboembolism

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FGG Gly191Arg — A Rare Fibrinogen Variant With High VTE Risk

Fibrinogen is the central protein of blood clot formation. When a vessel is damaged, thrombin cleaves fibrinogen into fibrin monomers that spontaneously polymerize into a mesh-like scaffold, which factor XIIIa then cross-links into a stable clot. The fibrinogen gamma chain (FGG)11 fibrinogen gamma chain (FGG)
encoded by the FGG gene on chromosome 4q32; the gamma chain forms the outer D-domain of fibrinogen, which mediates the polymerization contacts between fibrin monomers plays a critical structural role in this process. rs6063 introduces an arginine in place of glycine at position 191 of the gamma chain.

The Mechanism

ClinVar classifies the rs6063 T allele as pathogenic for Fibrinogen Milano XII in a digenic context — meaning this variant can act in concert with a second fibrinogen mutation to produce a named congenital fibrinopathy.

The Evidence

A prospective population-based cohort study (the Malmö Thrombophilia Study) genotyped common missense variants in fibrinogen genes in 1,465 VTE patients followed for approximately 10 years and 429 healthy controls22 A prospective population-based cohort study (the Malmö Thrombophilia Study) genotyped common missense variants in fibrinogen genes in 1,465 VTE patients followed for approximately 10 years and 429 healthy controls
Memon AA, Zöller B, Svensson PJ, Sundquist J, Sundquist K. Fibrinogen genotypes and their impact on recurrence of VTE and family history. Br J Haematol. 2025;206(2):657-665.. rs6063 was significantly associated with primary VTE: OR 8.2 (95% CI 1.05–63.6) after adjustment for age and sex. The wide confidence interval reflects the rarity of the T allele (~0.5% globally) and the resulting small number of T carriers in even large cohorts — but the direction of effect is clear and statistically significant.

Compound fibrinogen genotypes — where an index mutation interacts with common SNPs in the same or different fibrinogen genes — can amplify thrombogenic risk33 Compound fibrinogen genotypes — where an index mutation interacts with common SNPs in the same or different fibrinogen genes — can amplify thrombogenic risk
Bor et al. 2022 demonstrated that fibrin structural measures (fiber thickness, mass-to-length ratios) explain thrombotic phenotype variation that neither the index mutation alone nor SNPs alone predict. This is consistent with the ClinVar digenic classification of Fibrinogen Milano XII: the pathogenic phenotype requires rs6063 together with a second fibrinogen-gene variant.

Evidence level is moderate: a large prospective cohort demonstrating a significant association (OR 8.2), supported by consistent mechanistic understanding of dysfibrinogenemia, but limited to a single primary study specifically addressing this rsID with a wide confidence interval due to variant rarity.

Practical Actions

T allele carriers — virtually all of whom are heterozygous CT — have elevated VTE risk and should be aware of high-risk situations: prolonged immobility (long flights, hospitalization), surgery, oral contraceptives or hormone replacement therapy, pregnancy, and dehydration. Anticoagulation decisions require clinical evaluation by a hematologist or thrombosis specialist; anticoagulation after a first unprovoked VTE is typically extended if a thrombophilic variant is confirmed.

The raw OR of 8.2 should be understood in context: the baseline lifetime VTE risk is roughly 5–8% in the general population, so elevated relative risk remains rare in absolute terms. Thrombotic risk is also modified by concurrent thrombophilic variants (Factor V Leiden, prothrombin G20210A), lifestyle factors, and body weight.

Interactions

rs6063 has been classified as pathogenic for Fibrinogen Milano XII in a digenic context — meaning a second fibrinogen-gene variant (in trans) is required for the full named phenotype.

Concurrent Factor V Leiden (rs6025) or prothrombin G20210A (rs1799963) would compound thrombotic risk substantially — the intersection of a dysfibrinogenemia variant and an established thrombophilia warrants hematology evaluation rather than routine monitoring.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal

Common genotype — standard fibrinogen gamma chain function

You carry two copies of the common C allele at rs6063. This is the reference genotype, present in approximately 99% of people globally. Your fibrinogen gamma chain has the standard glycine at position 191, and fibrin polymerization proceeds normally from this variant's perspective. Your VTE risk is not elevated by rs6063.

CT Dysfibrinogenemia Carrier High Risk

Rare risk variant — significantly elevated primary VTE risk

The ClinVar classification "pathogenic for Fibrinogen Milano XII (digenic)" indicates that the full dysfibrinogenemia syndrome requires a second fibrinogen-gene variant in addition to rs6063 T. The heterozygous CT state alone is classified as uncertain significance for dysfibrinogenemia. The OR of 8.2 for primary VTE, while derived from a single prospective cohort (Malmö Thrombophilia Study, PMID 39828282), suggests the heterozygous state is clinically actionable even without a co-occurring second fibrinogen mutation.

TT Homozygous Risk High Risk

Two copies of the rare risk allele — very rare genotype

You carry two copies of the rare T allele at rs6063. The T allele frequency is approximately 0.5% globally, making the homozygous TT genotype vanishingly rare (estimated frequency under 0.003%). Both copies of your fibrinogen gamma chain carry the Gly191Arg substitution.