Congenital amegakaryocytic thrombocytopenia: genes and variants
Congenital amegakaryocytic thrombocytopenia is linked to 1 analyzed protein (MPL). 19 DNA variants are known to cause it; 166 more are uncertain, and 1 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: congenital amegakaryocytic thrombocytopenia 1
Genes linked to Congenital amegakaryocytic thrombocytopenia
MPL: Thrombopoietin receptor
Thrombopoietin signaling through this pathway drives megakaryocyte maturation, platelet production, and hematopoietic stem-cell maintenance. Activating variants can cause myeloproliferative neoplasms or hereditary thrombocytosis, whereas loss-of-function variants cause congenital amegakaryocytic thrombocytopenia.
19 disease-causing and 166 uncertain variants in MPL are linked to Congenital amegakaryocytic thrombocytopenia.
Known disease-causing variants in Congenital amegakaryocytic thrombocytopenia
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| MPL P136L | 136 | Extracellular | Disease-causing (★★) |
| MPL P136H | 136 | Extracellular | Disease-causing (★★) |
| MPL P136R | 136 | Extracellular | Disease-causing (★★) |
| MPL R257C | 257 | Fibronectin type-III 1 | Disease-causing (★★) |
| MPL F104S | 104 | Extracellular | Disease-causing (★★) |
| MPL W435C | 435 | Fibronectin type-III 2 | Disease-causing (★★) |
| MPL R102P | 102 | Extracellular | Disease-causing (★★) |
| MPL R102C | 102 | Extracellular | Disease-causing (★★) |
| MPL W154R | 154 | Extracellular | Disease-causing (★★) |
| MPL S505N | 505 | Transmembrane | Disease-causing (★★) |
| MPL P635L | 635 | Cytoplasmic | Disease-causing (★★) |
| MPL P106L | 106 | Extracellular | Disease-causing (★★) |
| MPL R257L | 257 | Fibronectin type-III 1 | Disease-causing (★) |
| MPL R102H | 102 | Extracellular | Disease-causing (★) |
| MPL W435R | 435 | Fibronectin type-III 2 | Disease-causing (★) |
| MPL L254P | 254 | Fibronectin type-III 1 | Disease-causing (★) |
| MPL Y69H | 69 | Extracellular | Disease-causing (★) |
| MPL G131R | 131 | Extracellular | Disease-causing (★) |
| MPL R426P | 426 | Fibronectin type-III 2 | Disease-causing (★) |
Uncertain variants in Congenital amegakaryocytic thrombocytopenia that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| MPL R257H | 257 | Fibronectin type-III 1 | Uncertain (★) | +6: 3 other pathogenic changes within 3 positions; R257C at the same position is pathogenic; REVEL 0.811 |
Which prediction tools work for Congenital amegakaryocytic thrombocytopenia
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- SIFT: 99 out of 100
- REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 96 out of 100
- CADD: 95 out of 100
- PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
Diseases related to Congenital amegakaryocytic thrombocytopenia
- Thrombocythemia 2, also linked to MPL
- Essential thrombocythemia, also linked to MPL
- Primary myelofibrosis, also linked to MPL
Frequently asked questions
Which genes are linked to Congenital amegakaryocytic thrombocytopenia?
In CATVariant, Congenital amegakaryocytic thrombocytopenia is linked to 1 analyzed protein: MPL (Thrombopoietin receptor).
How many genetic variants are linked to Congenital amegakaryocytic thrombocytopenia?
243 variants: 19 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 166 are of uncertain significance or have conflicting reports.
Which uncertain variants in Congenital amegakaryocytic thrombocytopenia look disease-causing?
1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example MPL R257H. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Congenital amegakaryocytic thrombocytopenia?
Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 18 disease-causing and 8 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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