FGF9
protein-codingfibroblast growth factor 9, the group of Receptor ligands|Fibroblast growth factor family
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~33.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0017923
Submitter: ClinGen
FGF9 was first reported in relation to autosomal dominant multiple synostoses syndrome in 2009 (Wu et al., PMID: 19589401). This condition is characterized by many synostoses, including sagittal craniosynostosis, as well as synostoses of elbows, hands, feet, and lumbar vertebrae. The condition also includes other skeletal anomalies (pectus excavatum, joint stiffness, recurrent sprains), crowded teeth, and cleft palate. 6 variants that have been reported in at least 20 probands in 6 publications (PMIDs: 19589401, 28730625, 33140402, 33174625, 35316564, 36980996) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (2 mouse models, expression-level evidence, interaction evidence; PMIDs: 11165488, 19219044, 21402782, 22123828, 28169396). Mouse models show that mutant mice have abnormal osteogenesis of coronal sutures, atypical expression of skeletal-related genes in the elbow joint, and joint fusions. Expression-level evidence shows expression in the palatal bone and the midfacial region. The gene is also shown to interact with TGFBR1 (ALK5) and TGFBR2, both of which are definitively associated with Loeys-Dietz Syndrome, which includes craniofacial features (bifid uvula, cleft palate, malar flattening, hypertelorism, strabismus, retrognathia) and skeletal features (joint dislocation/laxity, pectus excavatum, scoliosis, talipes equinovarus, pes planus). An important note is that none of the probands scored in this FGF9 curation have cardiac issues, which are a feature of Loeys-Dietz Syndrome. In summary, there is definitive evidence to support the relationship between FGF9 and autosomal dominant multiple synostoses syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 6/24/2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0013064
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013064
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013064
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0017923
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FGF9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002010.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 24 | 3 | 27 | |||
| missense | 3 | 2 | 25 | 3 | 1 | 34 |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 3 | 2 | 25 | 27 | 4 | 61 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002001.1 | 3 | MANE Select | |
| Ensembl | ENSP00000371790.5 | 3 | MANE Select | |
| Ensembl | ENSP00000811312.1 | 3 | Standard | |
| RefSeq | XP_011533298.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
- Melanoma - Homo sapiens (human)
- Breast cancer - Homo sapiens (human)
- Regulation of actin cytoskeleton - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- MAPK cascade
- angiogenesis
- osteoblast differentiation
- eye development
Molecular Function
- protein tyrosine kinase activity
- Ras guanyl-nucleotide exchange factor activity
- fibroblast growth factor receptor binding
- growth factor activity
- heparin binding
Cellular Component
- extracellular region
- basement membrane
- extracellular space
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000382353
- Coding exons
- 3
- Length
- 33116
- Individuals with no LoFs
- 125746
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125748
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.54 | 70 | 117 | 0.599 | 0.00000600 | 1345 |
| Missense (PolyPhen) | 12 | 39.883 | 0.30088 | 436 | ||
| Synonymous | -0.00622 | 51 | 50.9 | 1.00 | 0.00000274 | 415 |
| Loss of Function | 2.82 | 0 | 9.27 | 0.00 | 5.45e-7 | 107 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration. May have a role in glial cell growth and differentiation during development, gliosis during repair and regeneration of brain tissue after damage, differentiation and survival of neuronal cells, and growth stimulation of glial tumors. {ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:8663044}.;
- Disease
- DISEASE: Multiple synostoses syndrome 3 (SYNS3) [MIM:612961]: A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism. {ECO:0000269|PubMed:19589401}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.315
Intolerance Scores
- RVIS EVS
- 0.17
- RVIS percentile EVS
- 65.33
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.454
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |