HRAS

Chr 11AD

HRas proto-oncogene, GTPase

Also known as: C-BAS/HAS, C-H-RAS, C-HA-RAS1, CTLO, H-RASIDX, HAMSV, HRAS1, RASH1

NCBI Gene: 3265 ENSG00000174775 UniProt: P01112 OMIM: 190020

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene belongs to the Ras oncogene family, whose members are related to the transforming genes of mammalian sarcoma retroviruses. The products encoded by these genes function in signal transduction pathways. These proteins can bind GTP and GDP, and they have intrinsic GTPase activity. This protein undergoes a continuous cycle of de- and re-palmitoylation, which regulates its rapid exchange between the plasma membrane and the Golgi apparatus. Mutations in this gene cause Costello syndrome, a disease characterized by increased growth at the prenatal stage, growth deficiency at the postnatal stage, predisposition to tumor formation, cognitive disability, skin and musculoskeletal abnormalities, distinctive facial appearance and cardiovascular abnormalities. Defects in this gene are implicated in a variety of cancers, including bladder cancer, follicular thyroid cancer, and oral squamous cell carcinoma. Multiple transcript variants, which encode different isoforms, have been identified for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.937 OMIM phenotypes

VCEP Guidelines: RASopathyReleased

View Specifications ClinGen Panel

Clinical Summary— HRAS

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Gene-Disease Validity (ClinGen)

Costello syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.08) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

53 unique Pathogenic / Likely Pathogenic· 316 VUS of 741 total submissions

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Clinical Trials

10 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HRAS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.080

Z-score 1.72

OE 0.36 (0.16–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.51Z-score

OE missense 0.62 (0.51–0.75)

75 obs / 121.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.16–0.93)

0≤0.351.4

Missense OE?0.62 (0.51–0.75)

0≤0.61.4

Synonymous OE?1.40

0≤1.21.6

LoF obs/exp: 3 / 8.4Missense obs/exp: 75 / 121.9Syn Z: -2.27

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHRAS-related congenital myopathy with excess of muscle spindlesGOFAD

definitiveHRAS-related Costello syndromeGOFAD

This gene — mechanism propensity

0.85top 5%

GOF

0.85top 5%

LOF

0.3067th %ile

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.

GOFprediction above median · 1 literature citation · 91% of P/LP are missense

DNprediction above median · 1 literature citation

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

DNAnother mutant, the Ser17Arg variant, has been described as a dominant-negative form of p21 protein.1

GOFHeterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

741 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24

Likely Pathogenic29

VUS316

Likely Benign297

Benign43

Conflicting25

Pathogenic

Likely Pathogenic

316

VUS

297

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	23	0	0	24
Likely Pathogenic	1	25	3	0	29
VUS	40	233	41	2	316
Likely Benign	6	49	114	128	297
Benign	1	5	34	3	43
Conflicting	—				25
Total	49	335	192	133	734

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

27 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap HRAS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

HRAS · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — HRAS

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Gastric CancerHealthy

Preliminary Experimental Study on Key Technologies for Early Screening of Gastric Cancer

RECRUITING

NCT05991947Zhejiang Cancer HospitalStarted 2021-03-01

No intervention

Pancreatic CancerGastric CancerGastrointestinal Cancer

Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients

RECRUITING

NCT03190941Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2017-09-21

CyclophosphamideFludarabineAnti-KRAS G12V mTCR PBL

Non Small Cell Lung CancerEGFR Gene MutationALK Gene Mutation

Treatment Strategies and Survival Outcome for Non-small Cell Lung Cancer With Oncogenic Mutation

RECRUITING

NCT04322890Phase PHASE2Hunan Province Tumor HospitalStarted 2020-04-16

OsimertinibAlectinib 150 MGCrizotinib 250 MG

Colorectal Cancer Metastatic

Exploration of Therapeutic Strategies for NeoRAS Wild-type Metastatic Colorectal Cancer Based on Circulating Tumor DNA

RECRUITING

NCT06440902Phase PHASE2Fudan UniversityStarted 2023-12-28

Cetuximab

Advanced Malignant Solid NeoplasmAnn Arbor Stage III Non-Hodgkin LymphomaAnn Arbor Stage IV Non-Hodgkin Lymphoma

Targeted 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 RECRUITING

NCT03155620Phase PHASE2National Cancer Institute (NCI)Started 2017-07-31

Biopsy ProcedureBiospecimen CollectionBone Marrow Aspiration and Biopsy

Non-small Cell Lung CancerHistiocytic NeoplasmHistiocytosis

Phase 1/2 Trial of S241656 in Selected RAS/MAPK Mutation- Positive Malignancies

RECRUITING

NCT05786924Phase PHASE1, PHASE2Institut de Recherches Internationales ServierStarted 2023-04-18

S241656FOLFOX6/FOLFOX7FOLFIRI

Malignant Solid NeoplasmRecurrent Adrenal Gland PheochromocytomaRecurrent Ectomesenchymoma

Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial

ACTIVE NOT RECRUITING

NCT04284774Phase PHASE2National Cancer Institute (NCI)Started 2020-10-13

Tipifarnib

Malignant Solid Neoplasms

Adapting Treatment to the Tumor Molecular Alterations for Patients With Advanced Solid Tumors: MyOwnSpecificTreatment

RECRUITING

NCT02029001Phase PHASE2Centre Leon BerardStarted 2014-03

Nilotinib (400 mg BID)Everolimus (10 mg QD)Sorafenib (400 mg BID)

Colo-rectal CancerMolecular Pathway Deregulation

Clinicopathological Characteristics of Colon Cancer in Young Age

RECRUITING

NCT05365412Seoul National University Bundang HospitalStarted 2019-01-01