Achondroplasia: genes and variants

Genes linked to Achondroplasia

• 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.

  9 disease-causing and 17 uncertain variants in FGFR3 are linked to Achondroplasia.

Where Achondroplasia variants cluster

• FGFR3 Transmembrane (positions 376–396): 4 of 9 disease-causing changes, 17.1× more than its size predicts.

Known disease-causing variants in Achondroplasia

Which prediction tools work for Achondroplasia

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 84 out of 100

Same protein, different disease

• FGFR3-related chondrodysplasia is also caused by FGFR3 variants; they fall partly in the same places as the Achondroplasia variants (20 disease-causing).
• Hypochondroplasia is also caused by FGFR3 variants; they fall mostly in different places as the Achondroplasia variants (15 disease-causing).
• Thanatophoric dysplasia is also caused by FGFR3 variants; they fall partly in the same places as the Achondroplasia variants (8 disease-causing).
• Severe achondroplasia-developmental delay-acanthosis nigricans syndrome is also caused by FGFR3 variants; they fall in the same places as the Achondroplasia variants (5 disease-causing).
• Carcinoma of colon is also caused by FGFR3 variants; they fall mostly in different places as the Achondroplasia variants (3 disease-causing).

Diseases related to Achondroplasia

• Connective tissue disorder, also linked to FGFR3
• Colorectal cancer, also linked to FGFR3
• FGFR3-related chondrodysplasia, 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
• 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 Achondroplasia?

In CATVariant, Achondroplasia is linked to 1 analyzed protein: FGFR3 (Fibroblast growth factor receptor 3).

How many genetic variants are linked to Achondroplasia?

34 variants: 9 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 17 are of uncertain significance or have conflicting reports.

Which uncertain variants in Achondroplasia look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Achondroplasia?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.84, based on 9 disease-causing and 26 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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