FGFR3

Chr 4

fibroblast growth factor receptor 3

Also known as: ACH, CD333, CEK2, HSFGFR3EX, JTK4

NCBI Gene: 2261 ENSG00000068078 UniProt: P22607

The protein functions as a fibroblast growth factor receptor with a cytoplasmic tyrosine kinase domain that binds acidic and basic fibroblast growth factors and regulates bone development and maintenance through downstream signaling cascades. Mutations cause multiple skeletal dysplasias including achondroplasia, hypochondroplasia, thanatophoric dysplasia types I and II, and craniosynostosis syndromes such as Muenke syndrome and Crouzon syndrome with acanthosis nigricans, inherited in autosomal dominant or autosomal recessive patterns. The pathogenic mechanism involves gain-of-function mutations that disrupt normal bone and cartilage development.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]

GeneReviews ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.60

Clinical Summary— FGFR3

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Gene-Disease Validity (ClinGen)

Crouzon syndrome-acanthosis nigricans syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

7 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

49 unique Pathogenic / Likely Pathogenic· 411 VUS of 873 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FGFR3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.60LOEUF

pLI 0.000

Z-score 3.48

OE 0.39 (0.26–0.60)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.26Z-score

OE missense 0.85 (0.78–0.92)

458 obs / 540.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.26–0.60)

0≤0.351.4

Missense OE?0.85 (0.78–0.92)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 15 / 38.2Missense obs/exp: 458 / 540.2Syn Z: -3.39

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFGFR3-related achondroplasiaGOFAD

definitiveFGFR3-related camptodactyly tall stature and hearing loss syndromeOTHERAD

definitiveFGFR3-related thanatophoric dysplasia, type 1GOFAD

definitiveFGFR3-related thanatophoric dysplasia, type 2GOFAD

definitiveFGFR3-related hypochondroplasiaGOFAD

definitiveFGFR3-related Muenke syndromeGOFAD

definitiveFGFR3-related lacrimo-auriculo-dento-digital syndrome (LADD)OTHERAD

definitiveFGFR3-related Crouzon syndrome with acanthosis nigricansGOFAD

This gene — mechanism propensity

0.75top 25%

GOF

0.80top 10%

LOF

0.3164th %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 · 1 literature citation · 78% of P/LP are missense

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.

Literature Evidence

GOFAchondroplasia (ACH; MIM #100800) is an autosomal dominant genetic disease caused by gain-of-function mutations in FGFR3 gene and results in short-limb dwarfism.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 33848795 ↗

ClinVar Variant Classifications

873 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30

Likely Pathogenic19

VUS411

Likely Benign332

Benign29

Conflicting30

Pathogenic

Likely Pathogenic

411

VUS

332

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	24	0	0	30
Likely Pathogenic	5	14	0	0	19
VUS	22	357	22	10	411
Likely Benign	6	40	124	162	332
Benign	0	1	19	9	29
Conflicting	—				30
Total	39	436	165	181	851

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

View in ClinVar →

115 pathogenic / likely-pathogenic (of 123) ClinVar copy-number / structural variants overlap FGFR3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

FGFR3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — FGFR3

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Urinary Bladder NeoplasmsNeoplasm MetastasisUreteral Neoplasms

FORAGER-1: A Study of LOXO-435 (LY3866288) in Participants With Cancer With a Change in a Gene Called FGFR3

RECRUITING

NCT05614739Phase PHASE1Eli Lilly and CompanyStarted 2023-01-12

LOXO-435Pembrolizumabenfortumab vedotin

Locally Advanced Bladder Urothelial CarcinomaLocally Advanced Renal Pelvis Urothelial CarcinomaLocally Advanced Ureter Urothelial Carcinoma

Testing Combination Erdafitinib and Enfortumab Vedotin in Metastatic Bladder Cancer After Treatment With Chemotherapy and Immunotherapy

ACTIVE NOT RECRUITING

NCT04963153Phase PHASE1National Cancer Institute (NCI)Started 2022-07-07

Biospecimen CollectionBone ScanComputed Tomography

Glioblastoma, IDH-wildtype

Oxidative Phosphorylation Targeting In Malignant Glioma Using Metformin Plus Radiotherapy Temozolomide

RECRUITING

NCT04945148Phase PHASE2Hopital FochStarted 2024-05-10

MetforminRadiation IMRTTemozolomide

Lung Cancer

Feasibility of Targeted Bronchial Washing for Molecular Testing by Next Generation Sequencing in Early-stage Lung Cancer

ACTIVE NOT RECRUITING

NCT06301295Phase NAPusan National University HospitalStarted 2024-05-29

Ultarthin bronchoscopy with intratumoral washing

Locally Advanced Urothelial CarcinomaMetastatic Urothelial CarcinomaSolid Tumor

Safety and Preliminary Anti-Tumor Activity of TYRA-300 in Advanced Urothelial Carcinoma and Other Solid Tumors With FGFR3 Gene Alterations

ACTIVE NOT RECRUITING

NCT05544552Phase PHASE1, PHASE2Tyra Biosciences, IncStarted 2022-11-22

TYRA-300

Advanced Malignant Solid NeoplasmAnn Arbor Stage III Non-Hodgkin LymphomaAnn Arbor Stage IV Non-Hodgkin Lymphoma

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)

ACTIVE NOT RECRUITING

NCT03155620Phase PHASE2National Cancer Institute (NCI)Started 2017-07-31

Biopsy ProcedureBiospecimen CollectionBone Marrow Aspiration and Biopsy

Bladder CancerRecurrent Bladder CancerFGFR3 Gene Mutation

A Study of Oral Erdafitinib in People With Recurrent Non-Invasive Bladder Cancer

ACTIVE NOT RECRUITING

NCT04917809Phase PHASE2Memorial Sloan Kettering Cancer CenterStarted 2022-02-17

Erdafitinib

Low Grade Upper Tract Urothelial Carcinoma

Phase 2A/B Efficacy and Safety of Dabogratinib in Participants With Low Grade Upper Tract Urothelial Carcinoma

RECRUITING

NCT07265947Phase PHASE2Tyra Biosciences, IncStarted 2025-12-22