HRAS
Chr 11ADHRas proto-oncogene, GTPase
Also known as: C-BAS/HAS, C-H-RAS, C-HA-RAS1, CTLO, H-RASIDX, HAMSV, HRAS1, RASH1
The HRAS protein functions in signal transduction pathways by binding GTP and GDP with intrinsic GTPase activity, undergoing continuous cycles of palmitoylation that regulate its exchange between the plasma membrane and Golgi apparatus. Germline mutations cause Costello syndrome, an autosomal dominant disorder characterized by prenatal overgrowth followed by postnatal growth deficiency, cognitive disability, distinctive facial features, cardiovascular abnormalities, and tumor predisposition. The pathogenic mechanism involves gain-of-function mutations that disrupt normal cellular signaling.
Definitive — sufficient evidence for diagnostic panels
2 total gene-disease associations curated
Some data sources returned errors (1)
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Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
500 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 7 | 15 | 0 | 22 |
Likely Pathogenic | 0 | 8 | 6 | 0 | 14 |
VUS | 29 | 138 | 33 | 2 | 202 |
Likely Benign | 3 | 39 | 74 | 98 | 214 |
Benign | 0 | 1 | 28 | 0 | 29 |
Conflicting | — | 14 | |||
| Total | 32 | 193 | 156 | 100 | 495 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
HRAS · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Phase 1/2 Trial of S241656 in Selected RAS/MAPK Mutation- Positive Malignancies
RECRUITINGStudy of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)
RECRUITINGAdapting Treatment to the Tumor Molecular Alterations for Patients With Advanced Solid Tumors: MyOwnSpecificTreatment
RECRUITINGTreatment Strategies and Survival Outcome for Non-small Cell Lung Cancer With Oncogenic Mutation
RECRUITINGTipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
ACTIVE NOT RECRUITINGExploration of Therapeutic Strategies for NeoRAS Wild-type Metastatic Colorectal Cancer Based on Circulating Tumor DNA
RECRUITINGAdministering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients
RECRUITINGTargeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
ACTIVE NOT RECRUITINGClinicopathological Characteristics of Colon Cancer in Young Age
RECRUITINGPreliminary Experimental Study on Key Technologies for Early Screening of Gastric Cancer
RECRUITINGExternal Resources
Links to major genomics databases and tools