Maffucci syndrome: genes and variants
Maffucci syndrome is linked to 4 analyzed proteins (HIF1A, IDH1, IDH2 and COL2A1). 5 DNA variants are known to cause it; 6 more are uncertain, and 0 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Maffucci syndrome
HIF1A: Hypoxia-inducible factor 1-alpha
When oxygen falls, its stabilization activates transcriptional programs that increase glycolysis, angiogenesis, erythropoietic support, and other adaptations to hypoxia. Persistent HIF-1 signaling can help tumors survive oxygen-poor environments and contributes to ischemic and inflammatory disease biology.
2 disease-causing and 1 uncertain variants in HIF1A are linked to Maffucci syndrome.
IDH1: Isocitrate dehydrogenase [NADP] cytoplasmic
It normally generates alpha-ketoglutarate and NADPH in the cytosol and peroxisomes. Recurrent cancer-associated variants at R132 acquire the ability to produce D-2-hydroxyglutarate, an oncometabolite that rewires epigenetic regulation in glioma, leukemia, and other tumors.
1 disease-causing and 3 uncertain variants in IDH1 are linked to Maffucci syndrome.
IDH2: Isocitrate dehydrogenase [NADP], mitochondrial
It normally generates alpha-ketoglutarate and NADPH inside mitochondria. Recurrent R140 and R172 cancer-associated variants instead produce D-2-hydroxyglutarate, an oncometabolite that drives epigenetic dysregulation in acute myeloid leukemia and other tumors.
1 disease-causing and 0 uncertain variants in IDH2 are linked to Maffucci syndrome.
COL2A1: Collagen alpha-1(II) chain
It provides the principal fibrillar collagen framework of cartilage and is also important in the vitreous and inner ear. Pathogenic variants cause a broad type II collagenopathy spectrum including Stickler syndrome, spondyloepiphyseal dysplasia, and severe skeletal dysplasias.
1 disease-causing and 0 uncertain variants in COL2A1 are linked to Maffucci syndrome.
Weakly linked (only a few uncertain records): CDKN2A and VHL.
Known disease-causing variants in Maffucci syndrome
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| IDH1 R132C | 132 | Disease-causing (★★) | |
| IDH2 R172G | 172 | Disease-causing (★) | |
| COL2A1 E652G | 652 | Triple-helical region | Disease-causing (★) |
| HIF1A E457K | 457 | ODD | Disease-causing (★) |
| HIF1A A654V | 654 | ID | Disease-causing (★) |
Same protein, different disease
- Enchondromatosis is also caused by HIF1A variants; they fall mostly in different places as the Maffucci syndrome variants (3 disease-causing).
- D-2-hydroxyglutaric aciduria is also caused by IDH2 variants; they fall mostly in different places as the Maffucci syndrome variants (3 disease-causing).
- Spondyloepiphyseal dysplasia congenita is also caused by COL2A1 variants; they fall mostly in different places as the Maffucci syndrome variants (38 disease-causing).
- Achondrogenesis type II is also caused by COL2A1 variants; they fall mostly in different places as the Maffucci syndrome variants (34 disease-causing).
- Stickler syndrome is also caused by COL2A1 variants; they fall mostly in different places as the Maffucci syndrome variants (26 disease-causing).
- Spondyloepimetaphyseal dysplasia, Strudwick type is also caused by COL2A1 variants; they fall mostly in different places as the Maffucci syndrome variants (18 disease-causing).
- Connective tissue disorder is also caused by COL2A1 variants; they fall mostly in different places as the Maffucci syndrome variants (15 disease-causing).
Diseases related to Maffucci syndrome
- Acute myeloid leukemia, also linked to IDH1 and IDH2
- Enchondromatosis, also linked to HIF1A and IDH1
- Spondyloepiphyseal dysplasia congenita, also linked to COL2A1
- Achondrogenesis type II, also linked to COL2A1
- Stickler syndrome, also linked to COL2A1
- Connective tissue disorder, also linked to COL2A1
- Spondyloepimetaphyseal dysplasia, Strudwick type, also linked to COL2A1
- Type 2 collagenopathy, also linked to COL2A1
- Spondyloperipheral dysplasia, also linked to COL2A1
- Fetal anomalies with a likely genetic cause, also linked to COL2A1
- Vascular malformation, also linked to IDH2
- Spondyloepiphyseal dysplasia, Stanescu type, also linked to COL2A1
Frequently asked questions
Which genes are linked to Maffucci syndrome?
In CATVariant, Maffucci syndrome is linked to 4 analyzed proteins: HIF1A (Hypoxia-inducible factor 1-alpha), IDH1 (Isocitrate dehydrogenase [NADP] cytoplasmic), IDH2 (Isocitrate dehydrogenase [NADP], mitochondrial) and COL2A1 (Collagen alpha-1(II) chain).
How many genetic variants are linked to Maffucci syndrome?
12 variants: 5 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 6 are of uncertain significance or have conflicting reports.
Which uncertain variants in Maffucci syndrome look disease-causing?
None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.
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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