FGF9

Chr 13

fibroblast growth factor 9

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

NCBI Gene: 2254 ENSG00000102678 UniProt: P31371

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.

GeneReviews 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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtMultiple synostoses syndrome 3

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · multiple synostoses syndrome · AD · ClinGen 2025

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.32

LOEUF· LoF intol.

LOF

Mechanism· G2P

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GeneReview available — FGF9

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in FGF9?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 500

184 rare PASS variants

Rare truncating (LoF)

1 in 20,000

9 rare PASS variants

Rare synonymous (reference)

1 in 460

112 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FGF9. 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 960	1 in 27,000
South Asian	~43k	1 in 630	none seen
Remaining (unassigned)	~30k	1 in 300	none seen
European (Finnish)	~27k	≈ 1 in 27,000	1 in 3,800
Admixed American	~22k	1 in 660	none seen
African / African American	~21k	1 in 600	≈ 1 in 9,200
East Asian	~20k	1 in 1,300	≈ 1 in 20,000
Ashkenazi Jewish	~13k	≈ 1 in 4,400	none seen
Middle Eastern	~2,884	1 in 480	none seen

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 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓