FGF9

Chr 13AD

fibroblast growth factor 9

Also known as: FGF-9, GAF, HBFG-9, HBGF-9, SYNS3

NCBI Gene: 2254 ENSG00000102678 UniProt: P31371 OMIM: 600921

The protein is a secreted fibroblast growth factor that regulates embryonic development, cell proliferation and differentiation, and plays a key role in glial cell development and neuronal cell survival. Mutations cause multiple synostoses syndrome 3, characterized by progressive fusion of joints and bones, with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.95, LOEUF 0.32), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein was isolated as a secreted factor that exhibits a growth-stimulating effect on cultured glial cells. In nervous system, this protein is produced mainly by neurons and may be important for glial cell development. Expression of the mouse homolog of this gene was found to be dependent on Sonic hedgehog (Shh) signaling. Mice lacking the homolog gene displayed a male-to-female sex reversal phenotype, which suggested a role in testicular embryogenesis. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.321 OMIM phenotype

Clinical Summary— FGF9

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Gene-Disease Validity (ClinGen)

multiple synostoses syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 79 VUS of 155 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.947

Z-score 2.82

OE 0.00 (0.00–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.54Z-score

OE missense 0.60 (0.49–0.73)

70 obs / 116.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.32)

0≤0.351.4

Missense OE?0.60 (0.49–0.73)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 0 / 9.3Missense obs/exp: 70 / 116.9Syn Z: -0.01

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongFGF9-related multiple synostoses syndromeLOFAD

This gene — mechanism propensity

0.3793th %ile

GOF

0.6541th %ile

LOF

0.66top 25%

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

LOFprediction above median · 1 literature citation · LOEUF 0.32

GOFprediction 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

LOFImportantly, although other pro-osteogenic factors [Fgf-2, Fgf-18, and bone morphogenic protein 2 (Bmp-2)] still were present in Fgf-9(+/-) mice, they could not compensate for the haploinsufficiency of the Fgf-9 gene.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 20547837 ↗

ClinVar Variant Classifications

155 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS79

Likely Benign29

Benign40

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	0	2	0	0	2
VUS	0	25	54	0	79
Likely Benign	0	1	5	23	29
Benign	0	1	35	4	40
Conflicting	—				2
Total	0	32	94	27	155

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

View in ClinVar →

43 pathogenic / likely-pathogenic (of 53) ClinVar copy-number / structural variants overlap FGF9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →