F12

Chr 5ADAR

coagulation factor XII

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

Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa (PubMed:2019570, PubMed:21304106, PubMed:8427954)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Angioedema, hereditary, 3MIM #610618

Factor XII deficiencyMIM #234000

Clinical highlights

Gene–disease validity (ClinGen)

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

255

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.78

LOEUF

GOF

Mechanism· G2P

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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

Background carrier burden — how many people carry a rare variant somewhere in F12?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

853 rare PASS variants

Rare truncating (LoF)

1 in 610

144 rare PASS variants

Rare synonymous (reference)

1 in 150

406 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for F12. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 170	1 in 740
South Asian	~43k	1 in 65	1 in 690
Remaining (unassigned)	~30k	1 in 68	1 in 750
European (Finnish)	~27k	1 in 290	1 in 3,700
Admixed American	~22k	1 in 66	1 in 1,300
African / African American	~21k	1 in 83	1 in 590
East Asian	~20k	1 in 78	1 in 540
Ashkenazi Jewish	~13k	1 in 330	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 51	1 in 460

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 14 coding exons well covered in gnomAD exomes and genomes.? see exons ↓