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…

Primary Disease Associations & Inheritance

Colorectal cancer, somaticMIM #114500

Epidermal nevus, somaticMIM #162900

Melanocytic nevus syndrome, congenital, somaticMIM #137550

Neurocutaneous melanosis, somaticMIM #249400

Noonan syndrome 6MIM #613224

RAS-associated autoimmune lymphoproliferative syndrome type 1, somaticMIM #614470

Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaicMIM #163200

Thyroid carcinoma, follicular, somaticMIM #188470

UniProtLeukemia, juvenile myelomonocytic

UniProtMelanosis, neurocutaneous

UniProtKeratinocytic non-epidermolytic nevus

UniProtThyroid cancer, non-medullary, 2

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.61

LOEUF

GOF*

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in NRAS?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 1,000

155 rare PASS variants

Rare truncating (LoF)

1 in 15,000

20 rare PASS variants

Rare synonymous (reference)

1 in 470

85 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NRAS. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 1,200	1 in 13,000
South Asian	~43k	1 in 810	none seen
Remaining (unassigned)	~30k	1 in 1,200	none seen
European (Finnish)	~27k	1 in 3,800	≈ 1 in 13,000
Admixed American	~22k	1 in 1,400	none seen
African / African American	~21k	1 in 1,700	≈ 1 in 9,300
East Asian	~20k	1 in 680	none seen
Ashkenazi Jewish	~13k	1 in 1,300	none seen
Middle Eastern	~2,884	≈ 1 in 720	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

NRAS · protein map & ClinVar variants

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

VCEP specificationsRASopathyReleased

Specifications ↗Panel ↗

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

📖

GeneReview available — NRAS

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Colorectal Cancer

Tracking Mutations in Cell Free Tumour DNA to Predict Relapse in Early Colorectal Cancer

RECRUITING

NCT04050345Royal Marsden NHS Foundation TrustStarted 2016-12-05

Metastatic Colorectal Cancer

Cetuximab and Envafolimab Plus mFOLFOXIRI as First-line Treatment for RAS/BRAF Wild-type, MSS, Unresectable Left-side Metastatic Colorectal Cancer

RECRUITING

NCT05959356Phase PHASE2Sun Yat-sen UniversityStarted 2023-11-09

Cetuximab + Envafolimab + mFOLFOXIRICetuximab + mFOLFOX6

Colon AdenocarcinomaStage I Colon CancerStage II Colon Cancer

Postoperative Circulating Tumor DNA Monitoring in Stage I-III Driver-Mutant Colon Adenocarcinoma

RECRUITING

NCT07795528Ruijin HospitalStarted 2026-08-14

Longitudinal ctDNA-MRD NGS testing at scheduled postoperative time points

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

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

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