NRAS

Chr 1AD

NRAS proto-oncogene, GTPase

Also known as: ALPS4, CMNS, N-ras, NCMS, NRAS1, NS6, RALD1

NCBI Gene: 4893 ENSG00000213281 UniProt: P01111 OMIM: 164790

NRAS encodes a membrane-associated GTPase that shuttles between the Golgi apparatus and plasma membrane and functions in cellular signaling pathways. Germline mutations cause Noonan syndrome 6 with autosomal dominant inheritance, while somatic mutations result in various conditions including epidermal nevi, melanocytic nevus syndromes, and RAS-associated autoimmune lymphoproliferative syndrome. The gene is moderately constrained against loss-of-function variants (LOEUF 0.612), and both germline and somatic variants can affect multiple organ systems including cardiac, cutaneous, and hematologic.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This is an N-ras oncogene encoding a membrane protein that shuttles between the Golgi apparatus and the plasma membrane. This shuttling is regulated through palmitoylation and depalmitoylation by the ZDHHC9-GOLGA7 complex. The encoded protein, which has intrinsic GTPase activity, is activated by a guanine nucleotide-exchange factor and inactivated by a GTPase activating protein. Mutations in this gene have been associated with somatic rectal cancer, follicular thyroid cancer, autoimmune lymphoproliferative syndrome, Noonan syndrome, and juvenile myelomonocytic leukemia. [provided by RefSeq, Jun 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.618 OMIM phenotypes

VCEP Guidelines: RASopathyPilot

View Specifications ClinGen Panel

Clinical Summary— NRAS

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Gene-Disease Validity (ClinGen)

Costello syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

4 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.19) despite low pLI — interpret in context.

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ClinVar Variants

27 unique Pathogenic / Likely Pathogenic· 158 VUS of 350 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NRAS

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?

0.61LOEUF

pLI 0.490

Z-score 2.39

OE 0.19 (0.08–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.71Z-score

OE missense 0.53 (0.42–0.66)

55 obs / 104.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.08–0.61)

0≤0.351.4

Missense OE?0.53 (0.42–0.66)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 2 / 10.3Missense obs/exp: 55 / 104.2Syn Z: 0.01

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNRAS-related Noonan syndromeGOFAD

This gene — mechanism propensity

0.75top 25%

GOF

0.76top 25%

LOF

0.3745th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). 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 · 93% of P/LP are missense

DNprediction above median · 1 literature citation

LOF1 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

DNStructure of the dominant negative S17N mutant of Ras1

GOFActivating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous, and Costello syndrome, but activating germline mutations of NRAS have not been reported.2

LOF1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency.3

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

350 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic16

VUS158

Likely Benign101

Benign21

Conflicting17

Pathogenic

Likely Pathogenic

158

VUS

101

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	9	1	0	11
Likely Pathogenic	0	16	0	0	16
VUS	6	101	50	1	158
Likely Benign	0	1	57	43	101
Benign	0	0	19	2	21
Conflicting	—				17
Total	7	127	127	46	324

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap NRAS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

NRAS · 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 — NRAS

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Leukemia, Myeloid, AcuteRefractory AMLRelapsed Adult AML

Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tuspetinib (HM43239) in Patients With Relapsed or Refractory Acute Myeloid Leukemia

RECRUITING

NCT03850574Phase PHASE1, PHASE2Aptose Biosciences Inc.Started 2019-03-11

TuspetinibVenetoclax Oral TabletAzacitidine for Intravenous Infusion

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

Metastatic Colorectal Cancer (mCRC)Colorectal Neoplasms

Efficacy And Safety Of Hydroxychloroquine Combined With Methotrexate, Capecitabine And Bevacizumab Vs. Regorafenib In Participants With Refractory Metastatic Colorectal Cancer With Mutations In RAS Genes

RECRUITING

NCT06949982Phase PHASE2Sergey Orlov, MDStarted 2025-03-17

experimental group x-MAPRegorafenib (BAY 73-4506)

CancerMalignancies MultipleMalignant Solid Tumor

CAnadian CAncers With Rare Molecular Alterations (CARMA) - Basket Real-world Observational Study (BROS)

RECRUITING

NCT04151342University Health Network, TorontoStarted 2020-01-17

Cancer treatment with tyrosine kinase inhibitors (TKIs) or other molecularly targeted therapeutic agents.Patient-reported outcomes (PROs)

EGFR NP_005219.2:p.S492RKRAS Gene MutationMAP2K1 Gene Mutation

Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer

ACTIVE NOT RECRUITING

NCT03087071Phase PHASE2M.D. Anderson Cancer CenterStarted 2017-12-29

Laboratory Biomarker AnalysisPanitumumabTrametinib

OncologyMEK MutationRAF Gene Mutation

A Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors

RECRUITING

NCT06326411Phase PHASE1Nested Therapeutics, IncStarted 2024-04-09

NST-628

Colorectal Cancer

An Exploratory Study of Treatment Sensitivity and Prognostic Factors in a Efficacy and Safety Study of mFOLFOX6 + Bevacizumab Versus mFOLFOX6 + Panitumumab Therapy in Patients With Chemotherapy-naïve Unresectable Advanced or Recurrent Colorectal Cancer

ACTIVE NOT RECRUITING

NCT02394834TakedaStarted 2015-05-29

oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumaboxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, bevacizumab

Chronic Myeloid Leukemia, Chronic PhaseWithdrawal;Drug

Efficacy and Safety of TKIs' Withdrawal After a Two-step Dose Reduction in Patients with Chronic Myeloid Leukemia

ACTIVE NOT RECRUITING

NCT04147533Phase PHASE2Masaryk UniversityStarted 2020-06-16

Imatinib withdrawalDasatinibNilotinib

CRC (Colorectal Cancer)

PM8002 (BNT327) in Combination With Chemotherapy in Patients With Metastatic Colorectal Cancer

NOT YET RECRUITING

NCT07133750Phase PHASE2Biotheus Inc.Started 2025-08