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…

GOFmechanismAD/ARLOEUF 0.782 OMIM phenotypes

Clinical Summary— F12

🧬

Gene-Disease Validity (ClinGen)

congenital factor XII deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 116 VUS of 249 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.78LOEUF

pLI 0.000

Z-score 2.57

OE 0.52 (0.35–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.92Z-score

OE missense 0.86 (0.79–0.95)

307 obs / 356.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.52 (0.35–0.78)

0≤0.351.4

Missense OE?0.86 (0.79–0.95)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 17 / 32.9Missense obs/exp: 307 / 356.1Syn Z: 0.48

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveF12-related angioneurotic oedema, hereditary, with normal C1 inhibitor concentration and functionGOFAD

This gene — mechanism propensity

0.6452th %ile

GOF

0.6737th %ile

LOF

0.2874th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFThe data strongly suggested that T328K is a gain-of-function mutation that markedly increases F12 amadolytic activity but that does not alter F12 plasma levels.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 17186468 ↗

ClinVar Variant Classifications

249 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic11

VUS116

Likely Benign62

Benign18

Conflicting21

Pathogenic

Likely Pathogenic

116

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	5	0	0	9
Likely Pathogenic	10	1	0	0	11
VUS	2	96	9	9	116
Likely Benign	0	11	21	30	62
Benign	0	2	15	1	18
Conflicting	—				21
Total	16	115	45	40	237

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

57 pathogenic / likely-pathogenic (of 69) ClinVar copy-number / structural variants overlap F12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →