congenital factor XII deficiency

Summary

congenital factor XII deficiency (MONDO:0009315) is a disease caused by F12 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: F12 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 55
• Phenotypes (HPO): 9
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0003645	Prolonged partial thromboplastin time	Very frequent (80-99%)
HP:0004841	Reduced factor XII activity	Very frequent (80-99%)
HP:0001907	Thromboembolism	Occasional (5-29%)
HP:0001977	Abnormal thrombosis	Occasional (5-29%)
HP:0007985	Retinal arteriolar occlusion	Occasional (5-29%)
HP:0012636	Retinal vein occlusion	Occasional (5-29%)
HP:0200067	Recurrent spontaneous abortion	Occasional (5-29%)
HP:0001026	Penetrating foot ulcers	Very rare (<1-4%)
HP:0001892	Abnormal bleeding	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital factor XII deficiency
Mondo ID	MONDO:0009315
MeSH	D005175
OMIM	234000
Orphanet	330
DOID	DOID:2231
NCIT	C131740
SNOMED CT	46981006
UMLS	C0015526
MedGen	8772
GARD	0006558
NORD	1119
Is cancer (heuristic)	no

Also known as: coagulation factor 12 deficiency · congenital factor XII deficiency · congenital Hageman factor deficiency · factor 12 deficiency · Factor XII Deficiency · Hageman Factor deficiency

Data availability: 55 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › congenital factor XII deficiency

Related subtypes (7): autosomal dominant disease, autosomal recessive disease, septooptic dysplasia, camptodactyly-tall stature-scoliosis-hearing loss syndrome, brachydactyly-syndactyly syndrome, congenital factor XI deficiency, Weill-Marchesani syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

55 retrieved; paginated sample, class counts are floors:

17 conflicting classifications of pathogenicity, 17 uncertain significance, 6 likely pathogenic, 5 benign/likely benign, 4 pathogenic, 3 benign, 2 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1169	NM_000505.4(F12):c.983C>A (p.Thr328Lys)	F12	Pathogenic	criteria provided, multiple submitters, no conflicts
1170	NM_000505.4(F12):c.983C>G (p.Thr328Arg)	F12	Pathogenic	criteria provided, single submitter
3066136	NM_000505.4(F12):c.1570del (p.Val524fs)	F12	Pathogenic	criteria provided, single submitter
3381898	NM_000505.4(F12):c.303_304del (p.His101fs)	F12	Pathogenic	criteria provided, single submitter
441533	NM_000505.4(F12):c.971_1018+24del	F12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572132	NM_000505.4(F12):c.1517del (p.Gly506fs)	F12	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2671919	NM_000505.4(F12):c.415C>T (p.Gln139Ter)	F12	Likely pathogenic	criteria provided, single submitter
3381899	NM_000505.4(F12):c.1561G>A (p.Glu521Lys)	F12	Likely pathogenic	criteria provided, single submitter
3779632	NM_000505.4(F12):c.1375C>T (p.Gln459Ter)	F12	Likely pathogenic	criteria provided, single submitter
3779633	NM_000505.4(F12):c.1681-1G>C	F12	Likely pathogenic	criteria provided, single submitter
4849475	NM_000505.4(F12):c.1158C>A (p.Tyr386Ter)	F12	Likely pathogenic	criteria provided, single submitter
1166	NM_000505.4(F12):c.1681-1G>A	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352992	NM_000505.4(F12):c.1107G>C (p.Ser369=)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352993	NM_000505.4(F12):c.1025C>T (p.Pro342Leu)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352994	NM_000505.4(F12):c.1018+13G>C	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352995	NM_000505.4(F12):c.1018+12G>C	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353001	NM_000505.4(F12):c.418C>G (p.Leu140Val)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353003	NM_000505.4(F12):c.348C>A (p.Gly116=)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353004	NM_000505.4(F12):c.-3G>A	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
369462	NC_000005.10:g.177409584C>G	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904430	NM_000505.4(F12):c.1704G>A (p.Val568=)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904431	NM_000505.4(F12):c.1387+4C>G	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904493	NM_000505.4(F12):c.1018+11G>T	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904550	NM_000505.4(F12):c.129C>T (p.Thr43=)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904551	NM_000505.4(F12):c.120C>T (p.Leu40=)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905230	NM_000505.4(F12):c.1251-9C>A	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907810	NM_000505.4(F12):c.1018+14G>T	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907866	NM_000505.4(F12):c.293G>A (p.Cys98Tyr)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1168	NM_000505.4(F12):c.158A>G (p.Tyr53Cys)	F12	Uncertain significance	criteria provided, single submitter
2181485	NM_000505.4(F12):c.359T>A (p.Leu120His)	F12	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
F12	Strong	Autosomal recessive	congenital factor XII deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
F12	Orphanet:100054	F12-related hereditary angioedema with normal C1Inh
F12	Orphanet:330	Congenital factor XII deficiency
F12	Orphanet:617919	F12-associated cold autoinflammatory syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
F12	HGNC:3530	ENSG00000131187	P00748	Coagulation factor XII	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
F12	Coagulation factor XII	Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
F12	Protease	yes	3.4.21.38	Kringle, Fibronectin_type1, FN_type2_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingival epithelium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
F12	191	broad	marker	right lobe of liver, liver, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
F12	3,850

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
F12	P00748	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Aggregated β-amyloid induces FXII autocatalysis	1	5710.0×	7e-04	F12
Defective factor XII causes hereditary angioedema	1	2855.0×	7e-04	F12
Defective SERPING1 causes hereditary angioedema	1	2855.0×	7e-04	F12
Regulation of FXIIa and plasma kallikrein activity	1	1142.0×	0.001	F12
FXIIa, PKa-dependent activation of coagulation pathway	1	1142.0×	0.001	F12
FXIIa activates plasma kallikrein-kinin system	1	173.0×	0.006	F12

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
plasma kallikrein-kinin cascade	1	8426.0×	8e-04	F12
Factor XII activation	1	5617.3×	8e-04	F12
response to misfolded protein	1	5617.3×	8e-04	F12
positive regulation of fibrinolysis	1	3370.4×	1e-03	F12
blood coagulation, intrinsic pathway	1	2106.5×	0.001	F12
positive regulation of plasminogen activation	1	1872.4×	0.001	F12
positive regulation of blood coagulation	1	1123.5×	0.002	F12
fibrinolysis	1	842.6×	0.002	F12
zymogen activation	1	674.1×	0.002	F12
protein autoprocessing	1	648.1×	0.002	F12
blood coagulation	1	173.7×	0.006	F12
protein processing	1	170.2×	0.006	F12
innate immune response	1	33.6×	0.030	F12

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
F12	3	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NAFAMOSTAT	3	F12
GABEXATE	3	F12
SEPIMOSTAT	2	F12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
F12	128	Binding:123, Functional:3, ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
F12	3.4.21.38	coagulation factor XIIa

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
F12	128

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
NAFAMOSTAT	3	F12
GABEXATE	3	F12
SEPIMOSTAT	2	F12

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	F12
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02785718	Not specified	UNKNOWN	The Proteins of the Contact Activation System