Aneurysm-osteoarthritis syndrome: genes and variants
Aneurysm-osteoarthritis syndrome is linked to 1 analyzed protein (SMAD3). 18 DNA variants are known to cause it; 111 more are uncertain, and 5 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: Aneurysm - osteoarthritis syndrome
Genes linked to Aneurysm-osteoarthritis syndrome
SMAD3: SMAD family member 3
It carries TGF-beta receptor signals into the nucleus to control extracellular-matrix, differentiation, and growth programs. Heterozygous loss-of-function variants cause Loeys-Dietz syndrome type 3 with arterial aneurysm and dissection risk and often early osteoarthritis.
18 disease-causing and 111 uncertain variants in SMAD3 are linked to Aneurysm-osteoarthritis syndrome.
Known disease-causing variants in Aneurysm-osteoarthritis syndrome
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| SMAD3 M1I | 1 | Disease-causing (★★) | |
| SMAD3 M1L | 1 | Disease-causing (★★) | |
| SMAD3 M1T | 1 | Disease-causing (★★) | |
| SMAD3 R268H | 268 | MH2 | Disease-causing (★★) |
| SMAD3 R287Q | 287 | MH2 | Disease-causing (★★) |
| SMAD3 A112V | 112 | MH1 | Disease-causing (★★) |
| SMAD3 V331F | 331 | MH2 | Disease-causing (★★) |
| SMAD3 V122M | 122 | MH1 | Disease-causing (★★) |
| SMAD3 E239K | 239 | MH2 | Disease-causing (★★) |
| SMAD3 P263L | 263 | MH2 | Disease-causing (★★) |
| SMAD3 P68L | 68 | MH1 | Disease-causing (★★) |
| SMAD3 R243P | 243 | MH2 | Disease-causing (★) |
| SMAD3 I67S | 67 | MH1 | Disease-causing (★) |
| SMAD3 A112L | 112 | MH1 | Disease-causing (★) |
| SMAD3 R279K | 279 | MH2 | Disease-causing (★) |
| SMAD3 Q365L | 365 | MH2 | Disease-causing (★) |
| SMAD3 R386T | 386 | MH2 | Disease-causing (★) |
| SMAD3 S423T | 423 | MH2 | Disease-causing (★) |
Uncertain variants in Aneurysm-osteoarthritis syndrome that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| SMAD3 R243C | 243 | MH2 | Conflicting reports (★) | +6: in a 3D region that tolerates change poorly (1R); R243P at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.99 |
| SMAD3 P68S | 68 | MH1 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; P68L at the same position is pathogenic; seen in 6.9e-07 of gnomAD DNA copies; REVEL 0.676 |
| SMAD3 A112T | 112 | MH1 | Uncertain (★★) | +6: 2 other pathogenic changes within 3 positions; A112V at the same position is pathogenic; seen in 7.5e-06 of gnomAD DNA copies; REVEL 0.742 |
| SMAD3 A112D | 112 | MH1 | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; A112V at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.97 |
| SMAD3 P68A | 68 | MH1 | Uncertain (★★) | +6: 2 other pathogenic changes within 3 positions; P68L at the same position is pathogenic; seen in 1.4e-06 of gnomAD DNA copies; REVEL 0.674 |
Same protein, different disease
- Familial thoracic aortic aneurysm and aortic dissection is also caused by SMAD3 variants; they fall in the same places as the Aneurysm-osteoarthritis syndrome variants (28 disease-causing).
Diseases related to Aneurysm-osteoarthritis syndrome
- Familial thoracic aortic aneurysm and aortic dissection, also linked to SMAD3
- Ehlers-Danlos syndrome, also linked to SMAD3
- Loeys-Dietz syndrome, also linked to SMAD3
- Connective tissue disorder, also linked to SMAD3
Frequently asked questions
Which genes are linked to Aneurysm-osteoarthritis syndrome?
In CATVariant, Aneurysm-osteoarthritis syndrome is linked to 1 analyzed protein: SMAD3 (SMAD family member 3).
How many genetic variants are linked to Aneurysm-osteoarthritis syndrome?
137 variants: 18 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 111 are of uncertain significance or have conflicting reports.
Which uncertain variants in Aneurysm-osteoarthritis syndrome look disease-causing?
5 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SMAD3 R243C, SMAD3 P68S, SMAD3 A112T, SMAD3 A112D and SMAD3 P68A. These are leads for expert review, not diagnoses.
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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