F12

Chr 5ADAR

coagulation factor XII

Also known as: HAE3, HAEX, HAF

NCBI Gene: 2161 ENSG00000131187 UniProt: P00748 OMIM: 610619

Factor XII is a serum glycoprotein that initiates blood coagulation, fibrinolysis, and generates bradykinin and angiotensin by activating coagulation factors VII and XI. Mutations cause factor XII deficiency, which typically has no clinical symptoms despite prolonged clotting times, and hereditary angioedema type 3, which can follow either autosomal dominant or recessive inheritance patterns. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.775).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes coagulation factor XII which circulates in blood as a zymogen. This single chain zymogen is converted to a two-chain serine protease with an heavy chain (alpha-factor XIIa) and a light chain. The heavy chain contains two fibronectin-type domains, two epidermal growth factor (EGF)-like domains, a kringle domain and a proline-rich domain, whereas the light chain contains only a catalytic domain. On activation, further cleavages takes place in the heavy chain, resulting in the production of beta-factor XIIa light chain and the alpha-factor XIIa light chain becomes beta-factor XIIa heavy chain. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then to beta-factor XIIa. The active factor XIIa participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. It activates coagulation factors VII and XI. Defects in this gene do not cause any clinical symptoms and the sole effect is that whole-blood clotting time is prolonged. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Angioedema, hereditary, 3MIM #610618

Factor XII deficiencyMIM #234000

Clinical highlights

Gene-disease validity (ClinGen)

congenital factor XII deficiency · ARDefinitivesufficient evidence for diagnostic panels2 gene-disease associations curated in total

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

236

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.78

LOEUF

GOF

Mechanism· G2P