FGG

Chr 4

fibrinogen gamma chain

NCBI Gene: 2266 ENSG00000171557 UniProt: P02679

The gamma component of fibrinogen polymerizes with the alpha and beta chains to form fibrin, the primary structural component of blood clots essential for hemostasis and wound repair. Mutations cause congenital afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia, presenting with bleeding disorders of variable severity. Inheritance can be either autosomal recessive or autosomal dominant depending on the specific condition and mutation.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is the gamma component of fibrinogen, a blood-borne glycoprotein comprised of three pairs of nonidentical polypeptide chains. Following vascular injury, fibrinogen is cleaved by thrombin to form fibrin which is the most abundant component of blood clots. In addition, various cleavage products of fibrinogen and fibrin regulate cell adhesion and spreading, display vasoconstrictor and chemotactic activities, and are mitogens for several cell types. Mutations in this gene lead to several disorders, including dysfibrinogenemia, hypofibrinogenemia and thrombophilia. Alternative splicing results in transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.54

Clinical Summary— FGG

🧬

Gene-Disease Validity (ClinGen)

congenital fibrinogen deficiency · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

📋

ClinVar Variants

34 unique Pathogenic / Likely Pathogenic· 110 VUS of 210 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.050

Z-score 3.28

OE 0.29 (0.16–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.20Z-score

OE missense 0.78 (0.69–0.88)

184 obs / 235.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.16–0.54)

0≤0.351.4

Missense OE?0.78 (0.69–0.88)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 7 / 24.5Missense obs/exp: 184 / 235.8Syn Z: -0.14

This gene — mechanism propensity

0.6550th %ile

GOF

0.6639th %ile

LOF

0.2386th %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

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.

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

ClinVar Variant Classifications

210 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic19

VUS110

Likely Benign37

Benign12

Conflicting15

Pathogenic

Likely Pathogenic

110

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	5	4	0	15
Likely Pathogenic	6	12	1	0	19
VUS	2	97	8	3	110
Likely Benign	1	4	13	19	37
Benign	0	0	9	3	12
Conflicting	—				15
Total	15	118	35	25	208

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap FGG — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →