Congenital afibrinogenemia

Summary

Congenital afibrinogenemia (MONDO:0008737) is a disease caused by variants in FGA, FGB, and FGG, with 3 cohort genes and 6 clinical trials. The dominant Reactome pathway is Aggregated β-amyloid interacts with fibrinogen (3 cohort genes). Top therapeutic interventions include sodium chloride.

At a glance

• Causal genes: FGA (GenCC Definitive), FGB (GenCC Strong), FGG (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 270
• Phenotypes (HPO): 7
• Clinical trials: 6

Clinical features

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0000225	Gingival bleeding	Very frequent (80-99%)
HP:0000421	Epistaxis	Very frequent (80-99%)
HP:0001386	Joint swelling	Very frequent (80-99%)
HP:0001892	Abnormal bleeding	Very frequent (80-99%)
HP:0005268	Spontaneous abortion	Very frequent (80-99%)
HP:0400008	Menometrorrhagia	Very frequent (80-99%)
HP:0001342	Cerebral hemorrhage	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital afibrinogenemia
Mondo ID	MONDO:0008737
MeSH	D000347
OMIM	202400
Orphanet	98880
DOID	DOID:2236
NCIT	C98130
SNOMED CT	154818001
UMLS	C2584774
MedGen	749036
GARD	0005761
NORD	739
Is cancer (heuristic)	no

Also known as: afibrinogenemia · afibrinogenemia congenital · factor I deficiency

Data availability: 270 ClinVar variants · 7 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › coagulation protein disease › congenital fibrinogen deficiency › familial dysfibrinogenemia › congenital afibrinogenemia

Subtypes (2): familial hypofibrinogenemia, familial hypodysfibrinogenemia

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

270 retrieved; paginated sample, class counts are floors:

157 uncertain significance, 32 conflicting classifications of pathogenicity, 22 pathogenic, 22 benign, 12 benign/likely benign, 11 pathogenic/likely pathogenic, 10 likely pathogenic, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1098473	NM_000508.5(FGA):c.2155del (p.Gln719fs)	FGA	Pathogenic	criteria provided, single submitter
1322896	NM_021871.4(FGA):c.364+1G>A	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16399	NM_000508.3(FGA):c.103C>T (p.Arg35Cys)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16404	NM_021871.4(FGA):c.104G>A (p.Arg35His)	FGA	Pathogenic	criteria provided, multiple submitters, no conflicts
16410	NM_021871.4(FGA):c.1634A>T (p.Glu545Val)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16414	NC_000004.12:g.(154580323_154580329)_(154590210_154590216)del	FGA	Pathogenic	no assertion criteria provided
16415	NM_021871.4(FGA):c.510+1G>T	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16417	NM_021871.4(FGA):c.711dup (p.Lys238Ter)	FGA	Pathogenic	no assertion criteria provided
1684487	NM_021871.4(FGA):c.1055del (p.Pro352fs)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1696375	NM_021871.4(FGA):c.448C>T (p.Gln150Ter)	FGA	Pathogenic	criteria provided, multiple submitters, no conflicts
1803153	NM_021871.4(FGA):c.713del (p.Lys238fs)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3356488	NM_021871.4(FGA):c.1541del (p.Pro514fs)	FGA	Pathogenic	criteria provided, multiple submitters, no conflicts
3544392	NM_021871.4(FGA):c.180G>A (p.Trp60Ter)	FGA	Pathogenic	criteria provided, single submitter
402230	NM_021871.4(FGA):c.502C>T (p.Arg168Ter)	FGA	Pathogenic	criteria provided, multiple submitters, no conflicts
627216	NM_021871.4(FGA):c.117del (p.Val40fs)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
627406	NM_021871.4(FGA):c.922C>T (p.Arg308Ter)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632435	NM_021871.4(FGA):c.532C>T (p.Arg178Ter)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800649	NM_021871.4(FGA):c.811C>T (p.Arg271Ter)	FGA	Pathogenic	no assertion criteria provided
16389	NM_005141.5(FGB):c.1148T>G (p.Leu383Arg)	FGB	Pathogenic	no assertion criteria provided
16390	NM_005141.5(FGB):c.1289G>A (p.Gly430Asp)	FGB	Pathogenic	no assertion criteria provided
16392	NM_005141.5(FGB):c.958+13C>T	FGB	Pathogenic	no assertion criteria provided
16393	NM_005141.5(FGB):c.1244+1G>T	FGB	Pathogenic	no assertion criteria provided
16395	NM_005141.5(FGB):c.605T>A (p.Leu202Gln)	FGB	Pathogenic	no assertion criteria provided
16396	NM_005141.5(FGB):c.139C>T (p.Arg47Ter)	FGB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691428	NC_000004.11:g.(?155484162)(155493960_?)del	FGB	Pathogenic	criteria provided, single submitter
4847493	NM_005141.5(FGB):c.1372A>T (p.Lys458Ter)	FGB	Pathogenic	criteria provided, single submitter
800647	NM_005141.5(FGB):c.974G>C (p.Gly325Ala)	FGB	Pathogenic	no assertion criteria provided
16362	NM_021870.2(FGG):c.902G>A (p.Arg301His)	FGG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16377	NM_021870.3(FGG):c.307+5G>A	FGG	Pathogenic	no assertion criteria provided
16380	NM_021870.3(FGG):c.667-320A>T	FGG	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 29 · Orphanet: 13 · 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
FGA	Definitive	Autosomal recessive	congenital afibrinogenemia	14
FGB	Strong	Autosomal recessive	congenital afibrinogenemia	7
FGG	Strong	Autosomal recessive	congenital afibrinogenemia	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGA	Orphanet:101041	Familial hypofibrinogenemia
FGA	Orphanet:248408	Familial hypodysfibrinogenemia
FGA	Orphanet:93562	AFib amyloidosis
FGA	Orphanet:98880	Familial afibrinogenemia
FGA	Orphanet:98881	Familial dysfibrinogenemia
FGB	Orphanet:101041	Familial hypofibrinogenemia
FGB	Orphanet:248408	Familial hypodysfibrinogenemia
FGB	Orphanet:98880	Familial afibrinogenemia
FGB	Orphanet:98881	Familial dysfibrinogenemia
FGG	Orphanet:101041	Familial hypofibrinogenemia
FGG	Orphanet:248408	Familial hypodysfibrinogenemia
FGG	Orphanet:98880	Familial afibrinogenemia
FGG	Orphanet:98881	Familial dysfibrinogenemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FGA	HGNC:3661	ENSG00000171560	P02671	Fibrinogen alpha chain	gencc,clinvar
FGB	HGNC:3662	ENSG00000171564	P02675	Fibrinogen beta chain	gencc,clinvar
FGG	HGNC:3694	ENSG00000171557	P02679	Fibrinogen gamma chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGA	Fibrinogen alpha chain	Cleaved by the protease thrombin to yield monomers which, together with fibrinogen beta (FGB) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix.
FGB	Fibrinogen beta chain	Cleaved by the protease thrombin to yield monomers which, together with fibrinogen alpha (FGA) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix.
FGG	Fibrinogen gamma chain	Together with fibrinogen alpha (FGA) and fibrinogen beta (FGB), polymerizes to form an insoluble fibrin matrix.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGA	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_coil_dom, Fibrinogen_a/b/g_C_1
FGB	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_coil_dom, Fibrinogen_a/b/g_C_1
FGG	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_coil_dom, Fibrinogen_a/b/g_C_1

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	3
right lobe of liver	3
type B pancreatic cell	2
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGA	153	tissue_specific	marker	right lobe of liver, liver, islet of Langerhans
FGB	159	broad	marker	right lobe of liver, liver, type B pancreatic cell
FGG	157	broad	marker	right lobe of liver, liver, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGB	2,503
FGA	2,327
FGG	2,018

Intra-cohort edges

A	B	Sources
FGA	FGB	intact, string_interaction
FGA	FGG	biogrid_interaction, intact, string_interaction
FGB	FGG	biogrid_interaction, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGG	P02679	47
FGB	P02675	41
FGA	P02671	39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 3 evidence-associated genes (3 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 3 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 interacts with fibrinogen	3	2855.0×	4e-10	FGA, FGB, FGG
Fibrin formation	3	878.5×	1e-08	FGA, FGB, FGG
p130Cas linkage to MAPK signaling for integrins	3	761.3×	1e-08	FGA, FGB, FGG
GRB2:SOS provides linkage to MAPK signaling for Integrins	3	713.8×	1e-08	FGA, FGB, FGG
MyD88 deficiency (TLR2/4)	3	601.0×	2e-08	FGA, FGB, FGG
IRAK4 deficiency (TLR2/4)	3	571.0×	2e-08	FGA, FGB, FGG
Regulation of TLR by endogenous ligand	3	496.5×	2e-08	FGA, FGB, FGG
Integrin signaling	3	423.0×	3e-08	FGA, FGB, FGG
Signaling by high-kinase activity BRAF mutants	3	317.2×	7e-08	FGA, FGB, FGG
MAP2K and MAPK activation	3	285.5×	9e-08	FGA, FGB, FGG
Signaling by RAF1 mutants	3	278.5×	9e-08	FGA, FGB, FGG
Signaling by moderate kinase activity BRAF mutants	3	253.8×	9e-08	FGA, FGB, FGG
Paradoxical activation of RAF signaling by kinase inactive BRAF	3	253.8×	9e-08	FGA, FGB, FGG
Signaling downstream of RAS mutants	3	253.8×	9e-08	FGA, FGB, FGG
Signaling by BRAF and RAF1 fusions	3	170.4×	3e-07	FGA, FGB, FGG
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	3	152.3×	4e-07	FGA, FGB, FGG
Integrin cell surface interactions	3	134.3×	5e-07	FGA, FGB, FGG
ER-Phagosome pathway	3	129.8×	5e-07	FGA, FGB, FGG
Platelet degranulation	3	87.8×	2e-06	FGA, FGB, FGG
Post-translational protein phosphorylation	2	66.8×	3e-04	FGA, FGG
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	2	57.7×	4e-04	FGA, FGG
Amyloid fiber formation	1	34.3×	0.029	FGA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
blood coagulation, fibrin clot formation	3	1685.2×	2e-09	FGA, FGB, FGG
positive regulation of peptide hormone secretion	3	1532.0×	2e-09	FGA, FGB, FGG
plasminogen activation	3	1296.3×	2e-09	FGA, FGB, FGG
positive regulation of heterotypic cell-cell adhesion	3	1296.3×	2e-09	FGA, FGB, FGG
protein polymerization	3	991.3×	4e-09	FGA, FGB, FGG
fibrinolysis	3	842.6×	6e-09	FGA, FGB, FGG
positive regulation of vasoconstriction	3	601.9×	1e-08	FGA, FGB, FGG
positive regulation of exocytosis	3	601.9×	1e-08	FGA, FGB, FGG
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	3	581.1×	1e-08	FGA, FGB, FGG
negative regulation of endothelial cell apoptotic process	3	495.6×	2e-08	FGA, FGB, FGG
positive regulation of substrate adhesion-dependent cell spreading	3	374.5×	4e-08	FGA, FGB, FGG
positive regulation of protein secretion	3	343.9×	5e-08	FGA, FGB, FGG
platelet aggregation	3	337.0×	5e-08	FGA, FGB, FGG
response to calcium ion	3	318.0×	5e-08	FGA, FGB, FGG
cell-matrix adhesion	3	163.6×	4e-07	FGA, FGB, FGG
induction of bacterial agglutination	2	1872.4×	5e-07	FGA, FGB
protein-containing complex assembly	3	113.9×	9e-07	FGA, FGB, FGG
positive regulation of ERK1 and ERK2 cascade	3	85.1×	2e-06	FGA, FGB, FGG
blood coagulation, common pathway	1	2808.7×	4e-04	FGA
adaptive immune response	2	56.2×	5e-04	FGA, FGB
cellular response to leptin stimulus	1	510.7×	0.002	FGB
innate immune response	2	22.4×	0.003	FGA, FGB
cellular response to interleukin-1	1	93.6×	0.011	FGB
protein secretion	1	87.8×	0.011	FGG

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Fibrinogen, Human	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 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
FGB	1	2
FGA	0	0
FGG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SANGUINARIUM	2	FGB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FGB	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
SANGUINARIUM	2	FGB

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	FGB
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FGA, FGG

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FGA	0	FGB
FGG	0	FGB

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	3
PHASE4	1
PHASE2	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02822599	PHASE4	COMPLETED	Human Fibrinogen Concentrate in Pediatric Cardiac Surgery
NCT00916656	PHASE3	WITHDRAWN	Fibrinogen Concentrate (Human) - Efficacy and Safety Study
NCT02065882	PHASE3	COMPLETED	Pharmacokinetic, Efficacy and Safety of BT524 in Patients With Congenital Fibrinogen Deficiency
NCT04636268	PHASE3	WITHDRAWN	FIB Grifols Congenital Deficiency for On-demand Treatment and Surgical Prophylaxis
NCT01575756	PHASE2	COMPLETED	Pharmacokinetic, Efficacy, and Safety Study of Octafibrin Compared to Haemocomplettan/Riastap
NCT02281500	PHASE1/PHASE2	COMPLETED	Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived Fibrinogen (FIB Grifols) in Participants With Congenital Afibrinogenemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SODIUM CHLORIDE	4	1