RASopathy: genes and variants
RASopathy is linked to 13 analyzed proteins (PTPN11, BRAF, RAF1, KRAS, SOS1, MAP2K1, MAP2K2, CBL and 5 more). 212 DNA variants are known to cause it; 2,492 more are uncertain, and 10 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to RASopathy
PTPN11: Tyrosine-protein phosphatase non-receptor type 11
Its SHP2 phosphatase activity promotes RAS-MAPK signaling downstream of many receptor tyrosine kinases and cytokine receptors. Germline dysregulating variants cause Noonan-spectrum disorders, while somatic activating variants drive juvenile myelomonocytic leukemia and other cancers.
51 disease-causing and 218 uncertain variants in PTPN11 are linked to RASopathy.
BRAF: Serine/threonine-protein kinase B-raf
It relays activated RAS signals through MEK and ERK to control proliferation, differentiation, and survival. Activating variants, especially V600E, drive melanoma and several other cancers and create sensitivity to pathway-directed therapies.
36 disease-causing and 285 uncertain variants in BRAF are linked to RASopathy.
RAF1: RAF proto-oncogene serine/threonine-protein kinase
It relays activated RAS signals to MEK and ERK and also participates in survival and developmental pathways. Germline activating variants cause Noonan syndrome and related RASopathies, while oncogenic activation contributes to selected cancers.
28 disease-causing and 344 uncertain variants in RAF1 are linked to RASopathy.
KRAS: GTPase KRas
A small GTPase that acts as a molecular switch in the RAS-MAPK signaling pathway. By cycling between GDP- and GTP-bound states, it relays growth and survival signals, and activating KRAS variants are common drivers of cancer.
23 disease-causing and 37 uncertain variants in KRAS are linked to RASopathy.
SOS1: Son of sevenless homolog 1
It activates RAS by exchanging GDP for GTP downstream of receptor tyrosine kinases. Germline activating variants are a common cause of Noonan syndrome, while excessive SOS1-RAS signaling can contribute to cancer.
22 disease-causing and 537 uncertain variants in SOS1 are linked to RASopathy.
MAP2K1: Dual specificity mitogen-activated protein kinase kinase 1
It phosphorylates ERK1 and ERK2 downstream of RAF and thereby propagates RAS-MAPK growth and developmental signals. Activating somatic variants occur in several cancers, while germline activating variants can cause cardio-facio-cutaneous syndrome and related RASopathies.
14 disease-causing and 129 uncertain variants in MAP2K1 are linked to RASopathy.
MAP2K2: Dual specificity mitogen-activated protein kinase kinase 2
It works with MEK1 to activate ERK signaling downstream of RAS and RAF. Germline activating variants can cause cardio-facio-cutaneous syndrome, while acquired activation can support oncogenic MAPK signaling and drug resistance.
9 disease-causing and 261 uncertain variants in MAP2K2 are linked to RASopathy.
CBL: E3 ubiquitin-protein ligase CBL
It limits receptor-tyrosine-kinase signaling by ubiquitinating activated receptors and promoting their internalization and degradation. Germline or somatic pathogenic variants can prolong RAS-MAPK signaling and cause Noonan-like developmental disease or myeloid malignancy.
8 disease-causing and 608 uncertain variants in CBL are linked to RASopathy.
NRAS: GTPase NRas
Its active GTP-bound state drives RAF-MEK-ERK and PI3K signaling downstream of growth-factor receptors. Somatic activating variants are common drivers of melanoma, leukemia, and other cancers, while germline activating variants can cause Noonan syndrome.
6 disease-causing and 65 uncertain variants in NRAS are linked to RASopathy.
HRAS: GTPase HRas
Its GTP-bound state activates RAF-MEK-ERK and other pathways downstream of growth-factor receptors. Somatic activating variants drive several cancers, while germline activating variants cause Costello syndrome.
6 disease-causing and 2 uncertain variants in HRAS are linked to RASopathy.
RIT1: GTP-binding protein Rit1
It transmits growth and stress signals through RAS-MAPK and related pathways and is important in cardiovascular and nervous-system development. Germline activating variants cause Noonan syndrome, often with a high frequency of hypertrophic cardiomyopathy.
5 disease-causing and 2 uncertain variants in RIT1 are linked to RASopathy.
SOS2: Son of sevenless homolog 2
It activates RAS by catalyzing GDP-GTP exchange downstream of growth-factor receptors. Germline activating variants cause Noonan syndrome, generally through increased RAS-MAPK signaling.
3 disease-causing and 4 uncertain variants in SOS2 are linked to RASopathy.
SLC26A4: Pendrin
SLC26A4, known as pendrin, is an anion exchanger that transports chloride, iodide, and bicarbonate without directly using sodium. It supports ion balance in the inner ear and thyroid, and SLC26A4 variants cause Pendred syndrome and inherited deafness.
1 disease-causing and 0 uncertain variants in SLC26A4 are linked to RASopathy.
Weakly linked (only a few uncertain records): DDC.
Where RASopathy variants cluster
- CBL Linker (positions 352–380): 5 of 8 disease-causing changes, 19.5× more than its size predicts.
- BRAF Protein kinase (positions 457–717): 26 of 36 disease-causing changes, 2.1× more than its size predicts.
- PTPN11 SH2 1 (positions 6–102): 21 of 51 disease-causing changes, 2.5× more than its size predicts.
- BRAF Phorbol-ester/DAG-type (positions 234–280): 9 of 36 disease-causing changes, 4.1× more than its size predicts.
- CBL RING-type (positions 381–420): 3 of 8 disease-causing changes, 8.5× more than its size predicts.
Known disease-causing variants in RASopathy
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| HRAS A59G | 59 | Disease-causing (★★★★) | |
| MAP2K2 Y134C | 134 | Protein kinase | Disease-causing (★★★) |
| PTPN11 Y279C | 279 | Tyrosine-protein phosphatase | Disease-causing (★★★) |
| HRAS A59T | 59 | Disease-causing (★★★) | |
| MAP2K2 Y134H | 134 | Protein kinase | Disease-causing (★★★) |
| BRAF T241K | 241 | Phorbol-ester/DAG-type | Disease-causing (★★★) |
| BRAF G464E | 464 | Protein kinase | Disease-causing (★★★) |
| BRAF L485S | 485 | Protein kinase | Disease-causing (★★★) |
| BRAF L485F | 485 | Protein kinase | Disease-causing (★★★) |
| BRAF T599I | 599 | Protein kinase | Disease-causing (★★★) |
| BRAF T599R | 599 | Protein kinase | Disease-causing (★★★) |
| HRAS T58I | 58 | Disease-causing (★★★) | |
| HRAS A59L | 59 | Disease-causing (★★★) | |
| KRAS K5N | 5 | Disease-causing (★★★) | |
| KRAS V14I | 14 | Disease-causing (★★★) | |
| KRAS Q22R | 22 | Disease-causing (★★★) | |
| NRAS G12S | 12 | Disease-causing (★★★) | |
| NRAS G60E | 60 | Disease-causing (★★★) | |
| PTPN11 T52I | 52 | SH2 1 | Disease-causing (★★★) |
| PTPN11 Y62D | 62 | SH2 1 | Disease-causing (★★★) |
| PTPN11 E69Q | 69 | SH2 1 | Disease-causing (★★★) |
| PTPN11 L261F | 261 | Tyrosine-protein phosphatase | Disease-causing (★★★) |
| PTPN11 L261H | 261 | Tyrosine-protein phosphatase | Disease-causing (★★★) |
| PTPN11 A461G | 461 | Tyrosine-protein phosphatase | Disease-causing (★★★) |
| PTPN11 A461V | 461 | Tyrosine-protein phosphatase | Disease-causing (★★★) |
| PTPN11 A461T | 461 | Tyrosine-protein phosphatase | Disease-causing (★★★) |
| PTPN11 Q510P | 510 | Tyrosine-protein phosphatase | Disease-causing (★★★) |
| PTPN11 Q510H | 510 | Tyrosine-protein phosphatase | Disease-causing (★★★) |
| RAF1 R256S | 256 | Disease-causing (★★★) | |
| RAF1 S257P | 257 | Disease-causing (★★★) | |
| RAF1 S259Y | 259 | Disease-causing (★★★) | |
| RAF1 S259A | 259 | Disease-causing (★★★) | |
| RAF1 S259T | 259 | Disease-causing (★★★) | |
| RAF1 V263G | 263 | Disease-causing (★★★) | |
| SOS2 M267K | 267 | DH | Disease-causing (★★★) |
| PTPN11 K70R | 70 | SH2 1 | Disease-causing (★★★) |
| PTPN11 R265Q | 265 | Tyrosine-protein phosphatase | Disease-causing (★★★) |
| RIT1 M90V | 90 | Disease-causing (★★★) | |
| BRAF G265R | 265 | Phorbol-ester/DAG-type | Disease-causing (★★★) |
| BRAF G469E | 469 | Protein kinase | Disease-causing (★★★) |
| BRAF C532Y | 532 | Protein kinase | Disease-causing (★★★) |
| BRAF D594V | 594 | Protein kinase | Disease-causing (★★★) |
| BRAF F595L | 595 | Protein kinase | Disease-causing (★★★) |
| BRAF G596V | 596 | Protein kinase | Disease-causing (★★★) |
| BRAF V600G | 600 | Protein kinase | Disease-causing (★★★) |
| KRAS S65I | 65 | Disease-causing (★★★) | |
| MAP2K1 L42R | 42 | Disease-causing (★★★) | |
| MAP2K1 N122D | 122 | Protein kinase | Disease-causing (★★★) |
| PTPN11 G464A | 464 | Tyrosine-protein phosphatase | Disease-causing (★★★) |
| RAF1 T491I | 491 | Protein kinase | Disease-causing (★★★) |
| SOS1 R552S | 552 | Disease-causing (★★★) | |
| HRAS K117R | 117 | Disease-causing (★★★) | |
| MAP2K1 L42F | 42 | Disease-causing (★★★) | |
| NRAS I24N | 24 | Disease-causing (★★★) | |
| NRAS T50I | 50 | Disease-causing (★★★) | |
| PTPN11 Q506P | 506 | Tyrosine-protein phosphatase | Disease-causing (★★★) |
| KRAS D154V | 154 | Disease-causing (★★★) | |
| MAP2K1 F53S | 53 | Disease-causing (★★★) | |
| MAP2K1 K57Q | 57 | Disease-causing (★★★) | |
| MAP2K1 L92R | 92 | Protein kinase | Disease-causing (★★★) |
Showing 60 of 212.
Uncertain variants in RASopathy that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| CBL H398Y | 398 | RING-type | Conflicting reports (★) | +7: in a 3D region that tolerates change poorly (3R); H398N at the same position is pathogenic; seen in 0 of gnomAD DNA copies; REVEL 0.943 |
| CBL R420P | 420 | RING-type | Conflicting reports (★) | +7: 2 other pathogenic changes within 3 positions; R420L at the same position is pathogenic; seen in 0 of gnomAD DNA copies; REVEL 0.872 |
| CBL H398R | 398 | RING-type | Conflicting reports (★) | +7: in a 3D region that tolerates change poorly (3R); H398N at the same position is pathogenic; seen in 1.4e-06 of gnomAD DNA copies; REVEL 0.951 |
| SOS1 M269V | 269 | DH | Conflicting reports (★) | +7: 4 other pathogenic changes within 3 positions; M269R at the same position is pathogenic; seen in 1.4e-06 of gnomAD DNA copies; REVEL 0.788 |
| CBL R420G | 420 | RING-type | Uncertain (★) | +7: 2 other pathogenic changes within 3 positions; R420L at the same position is pathogenic; seen in 0 of gnomAD DNA copies; REVEL 0.955 |
| MAP2K1 R108Q | 108 | Protein kinase | Uncertain (★★) | +6: 2 other pathogenic changes within 3 positions; R108L at the same position is pathogenic; seen in 7.5e-06 of gnomAD DNA copies; REVEL 0.728 |
| SOS1 T266A | 266 | DH | Uncertain (★) | +6: 4 other pathogenic changes within 3 positions; T266P at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.94 |
| MAP2K2 V64A | 64 | Uncertain (★★) | +6: 3 other pathogenic changes within 3 positions; V64F at the same position is pathogenic; seen in 7.5e-06 of gnomAD DNA copies; REVEL 0.717 | |
| MAP2K1 N122H | 122 | Protein kinase | Uncertain (★) | +6: 3 other pathogenic changes within 3 positions; N122D at the same position is pathogenic; seen in 6.8e-07 of gnomAD DNA copies; REVEL 0.654 |
| SOS1 K728T | 728 | N-terminal Ras-GEF | Uncertain (★★) | +6: 2 other pathogenic changes within 3 positions; K728I at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.99 |
Which prediction tools work for RASopathy
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- AlphaGenome (regulatory): 99 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)
- AlphaMissense: 95 out of 100
- CATVariant: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MetaLR: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 85 out of 100
- MutPred2: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- EVE: 78 out of 100
- SIFT: 76 out of 100
- phyloP: 70 out of 100
- DMS / MaveDB: 61 out of 100
- AlphaGenome (splicing): 55 out of 100 (learned from overlapping clinical labels, so this is optimistic)
Same protein, different disease
- Noonan syndrome is also caused by PTPN11 variants; they fall partly in the same places as the RASopathy variants (44 disease-causing).
- Noonan syndrome and Noonan-related syndrome is also caused by PTPN11 variants; they fall partly in the same places as the RASopathy variants (29 disease-causing).
- LEOPARD syndrome 1 is also caused by PTPN11 variants; they fall partly in the same places as the RASopathy variants (16 disease-causing).
- Metachondromatosis is also caused by PTPN11 variants; they fall in the same places as the RASopathy variants (11 disease-causing).
- Monogenic short statue is also caused by PTPN11 variants; they fall in the same places as the RASopathy variants (6 disease-causing).
- Cardio-facio-cutaneous syndrome is also caused by BRAF variants; they fall in the same places as the RASopathy variants (26 disease-causing).
- Cardiofaciocutaneous syndrome is also caused by BRAF variants; they fall partly in the same places as the RASopathy variants (17 disease-causing).
- Noonan syndrome is also caused by BRAF variants; they fall in the same places as the RASopathy variants (11 disease-causing).
- Noonan syndrome and Noonan-related syndrome is also caused by BRAF variants; they fall in the same places as the RASopathy variants (10 disease-causing).
- Non-small cell lung carcinoma is also caused by BRAF variants; they fall in the same places as the RASopathy variants (9 disease-causing).
- Noonan syndrome is also caused by RAF1 variants; they fall partly in the same places as the RASopathy variants (14 disease-causing).
- Dilated cardiomyopathy 1NN is also caused by RAF1 variants; they fall partly in the same places as the RASopathy variants (5 disease-causing).
- LEOPARD syndrome 1 is also caused by RAF1 variants; they fall in the same places as the RASopathy variants (4 disease-causing).
- Noonan syndrome is also caused by KRAS variants; they fall in the same places as the RASopathy variants (16 disease-causing).
- Cardiofaciocutaneous syndrome is also caused by KRAS variants; they fall in the same places as the RASopathy variants (9 disease-causing).
- Autoimmune lymphoproliferative syndrome is also caused by KRAS variants; they fall partly in the same places as the RASopathy variants (5 disease-causing).
- Non-small cell lung carcinoma is also caused by KRAS variants; they fall partly in the same places as the RASopathy variants (5 disease-causing).
- Cardio-facio-cutaneous syndrome is also caused by KRAS variants; they fall in the same places as the RASopathy variants (4 disease-causing).
- Noonan syndrome is also caused by SOS1 variants; they fall partly in the same places as the RASopathy variants (30 disease-causing).
- Noonan syndrome and Noonan-related syndrome is also caused by SOS1 variants; they fall partly in the same places as the RASopathy variants (9 disease-causing).
- Fibromatosis, gingival, 1 is also caused by SOS1 variants; they fall partly in the same places as the RASopathy variants (4 disease-causing).
- Cardiofaciocutaneous syndrome is also caused by MAP2K1 variants; they fall in the same places as the RASopathy variants (14 disease-causing).
- Cardio-facio-cutaneous syndrome is also caused by MAP2K1 variants; they fall partly in the same places as the RASopathy variants (6 disease-causing).
Diseases related to RASopathy
- Noonan syndrome, also linked to BRAF, CBL, HRAS, KRAS and 8 more
- Noonan syndrome and Noonan-related syndrome, also linked to BRAF, CBL, HRAS, KRAS and 8 more
- Hypertrophic cardiomyopathy, also linked to BRAF, HRAS, MAP2K1, MAP2K2 and 1 more
- Cardiofaciocutaneous syndrome, also linked to BRAF, KRAS, MAP2K1, MAP2K2 and 1 more
- Costello syndrome, also linked to BRAF, HRAS, MAP2K1, MAP2K2 and 1 more
- Cardio-facio-cutaneous syndrome, also linked to BRAF, KRAS, MAP2K1 and MAP2K2
- Vascular malformation, also linked to BRAF, KRAS, MAP2K1 and NRAS
- Juvenile myelomonocytic leukemia, also linked to CBL, KRAS, NRAS and PTPN11
- Melanoma, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
- Acute myeloid leukemia, also linked to KRAS, NRAS and PTPN11
- LEOPARD syndrome 1, also linked to BRAF, PTPN11 and RAF1
- Colorectal cancer, also linked to BRAF, KRAS and NRAS
Frequently asked questions
Which genes are linked to RASopathy?
In CATVariant, RASopathy is linked to 13 analyzed proteins: PTPN11 (Tyrosine-protein phosphatase non-receptor type 11), BRAF (Serine/threonine-protein kinase B-raf), RAF1 (RAF proto-oncogene serine/threonine-protein kinase), KRAS (GTPase KRas), SOS1 (Son of sevenless homolog 1), MAP2K1 (Dual specificity mitogen-activated protein kinase kinase 1) and 7 more.
How many genetic variants are linked to RASopathy?
2,916 variants: 212 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2,492 are of uncertain significance or have conflicting reports.
Which uncertain variants in RASopathy look disease-causing?
10 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CBL H398Y, CBL R420P, CBL H398R, SOS1 M269V and CBL R420G. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for RASopathy?
Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 157 disease-causing and 70 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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