FGFR3-related chondrodysplasia: genes and variants
FGFR3-related chondrodysplasia is linked to 1 analyzed protein (FGFR3). 20 DNA variants are known to cause it; 107 more are uncertain, and 5 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to FGFR3-related chondrodysplasia
FGFR3: Fibroblast growth factor receptor 3
It normally restrains growth-plate chondrocyte proliferation while regulating multiple developmental pathways. Activating germline variants cause achondroplasia and related skeletal dysplasias, while somatic activating alterations are common in bladder cancer and some other tumors.
20 disease-causing and 107 uncertain variants in FGFR3 are linked to FGFR3-related chondrodysplasia.
Where FGFR3-related chondrodysplasia variants cluster
- FGFR3 Ig-like C2-type 3 (positions 253–355): 4 of 20 disease-causing changes, 1.6× more than its size predicts.
Known disease-causing variants in FGFR3-related chondrodysplasia
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| FGFR3 R248C | 248 | Extracellular | Disease-causing (★★★★) |
| FGFR3 N540D | 540 | Protein kinase | Disease-causing (★★) |
| FGFR3 N540T | 540 | Protein kinase | Disease-causing (★★) |
| FGFR3 N540S | 540 | Protein kinase | Disease-causing (★★) |
| FGFR3 N540K | 540 | Protein kinase | Disease-causing (★★) |
| FGFR3 K650Q | 650 | Protein kinase | Disease-causing (★★) |
| FGFR3 K650N | 650 | Protein kinase | Disease-causing (★★) |
| FGFR3 R621H | 621 | Protein kinase | Disease-causing (★★) |
| FGFR3 S249C | 249 | Extracellular | Disease-causing (★★) |
| FGFR3 Y278C | 278 | Ig-like C2-type 3 | Disease-causing (★★) |
| FGFR3 S279C | 279 | Ig-like C2-type 3 | Disease-causing (★★) |
| FGFR3 S344C | 344 | Ig-like C2-type 3 | Disease-causing (★★) |
| FGFR3 S348C | 348 | Ig-like C2-type 3 | Disease-causing (★★) |
| FGFR3 Y373C | 373 | Extracellular | Disease-causing (★★) |
| FGFR3 G375C | 375 | Extracellular | Disease-causing (★★) |
| FGFR3 G380R | 380 | Transmembrane | Disease-causing (★★) |
| FGFR3 S371C | 371 | Extracellular | Disease-causing (★★) |
| FGFR3 N428S | 428 | Cytoplasmic | Disease-causing (★★) |
| FGFR3 T546K | 546 | Protein kinase | Disease-causing (★) |
| FGFR3 P550H | 550 | Protein kinase | Disease-causing (★) |
Uncertain variants in FGFR3-related chondrodysplasia that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| FGFR3 S249Y | 249 | Extracellular | Conflicting reports (★) | +7: 2 other pathogenic changes within 3 positions; S249C at the same position is pathogenic; seen in 4.8e-06 of gnomAD DNA copies; REVEL 0.853 |
| FGFR3 R621C | 621 | Protein kinase | Conflicting reports (★) | +6: in a 3D region that tolerates change poorly (1A); R621H at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 1.00 |
| FGFR3 S249F | 249 | Extracellular | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; S249C at the same position is pathogenic; REVEL 0.817 |
| FGFR3 R621L | 621 | Protein kinase | Uncertain (★★) | +6: in a 3D region that tolerates change poorly (1A); R621H at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 1.00 |
| FGFR3 K650E | 650 | Protein kinase | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; K650Q at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.98 |
Which prediction tools work for FGFR3-related chondrodysplasia
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- REVEL: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 90 out of 100
- SIFT: 88 out of 100
- phyloP: 67 out of 100
Same protein, different disease
- Hypochondroplasia is also caused by FGFR3 variants; they fall partly in the same places as the FGFR3-related chondrodysplasia variants (15 disease-causing).
- Achondroplasia is also caused by FGFR3 variants; they fall in the same places as the FGFR3-related chondrodysplasia variants (9 disease-causing).
- Thanatophoric dysplasia is also caused by FGFR3 variants; they fall partly in the same places as the FGFR3-related chondrodysplasia variants (8 disease-causing).
- Malignant tumor of urinary bladder is also caused by FGFR3 variants; they fall mostly in different places as the FGFR3-related chondrodysplasia variants (3 disease-causing).
Diseases related to FGFR3-related chondrodysplasia
- Connective tissue disorder, also linked to FGFR3
- Colorectal cancer, also linked to FGFR3
- Malignant tumor of urinary bladder, also linked to FGFR3
- Hypochondroplasia, also linked to FGFR3
- Carcinoma of colon, also linked to FGFR3
- Achondroplasia, also linked to FGFR3
- Thanatophoric dysplasia, also linked to FGFR3
- Common craniosynostosis syndromes, also linked to FGFR3
- Levy-Hollister syndrome, also linked to FGFR3
- Severe achondroplasia-developmental delay-acanthosis nigricans syndrome, also linked to FGFR3
- Renal cell carcinoma, also linked to FGFR3
- Craniosynostosis syndrome, also linked to FGFR3
Frequently asked questions
Which genes are linked to FGFR3-related chondrodysplasia?
In CATVariant, FGFR3-related chondrodysplasia is linked to 1 analyzed protein: FGFR3 (Fibroblast growth factor receptor 3).
How many genetic variants are linked to FGFR3-related chondrodysplasia?
135 variants: 20 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 107 are of uncertain significance or have conflicting reports.
Which uncertain variants in FGFR3-related chondrodysplasia look disease-causing?
5 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example FGFR3 S249Y, FGFR3 R621C, FGFR3 S249F, FGFR3 R621L and FGFR3 K650E. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for FGFR3-related chondrodysplasia?
Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.90, based on 10 disease-causing and 25 harmless variants).
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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