KRAS

Chr 12

KRas proto-oncogene, GTPase

Also known as: 'C-K-RAS, C-K-RAS, CFC2, K-RAS2A, K-RAS2B, K-RAS4A, K-RAS4B, K-Ras

NCBI Gene: 3845 ENSG00000133703 UniProt: P01116

The KRAS protein is a small GTPase that regulates cell signaling pathways controlling cell growth and differentiation. Germline mutations cause autosomal dominant neurodevelopmental disorders including Noonan syndrome 3 and cardiofaciocutaneous syndrome 2, while somatic mutations lead to various cancers and RAS-associated autoimmune leukoproliferative disorder. The pathogenic mechanism involves dominant-negative effects from activating mutations, typically single amino acid substitutions that disrupt normal GTPase function.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Alternative splicing leads to variants encoding two isoforms that differ in the C-terminal region. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtLeukemia, acute myelogenous

UniProtLeukemia, juvenile myelomonocytic

UniProtNoonan syndrome 3

UniProtGastric cancer

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · Noonan syndrome · AD · ClinGen 2018
Definitive · Noonan syndrome 3 · AD · Ambry Genetics
Definitive · cardiofaciocutaneous syndrome 2 · AD · G2P
Strong · cardiofaciocutaneous syndrome · AD · ClinGen 2018
Disputed · Costello syndrome · AD · ClinGen 2018 — evidence questions this relationship

+2 more curated pairs

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

4724

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.24

LOEUF

GOF*

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.24LOEUF

pLI 0.001

Z-score 1.06

OE 0.63 (0.34–1.24)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

2.32Z-score

OE missense 0.34 (0.26–0.45)

33 obs / 97.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.63 (0.34–1.24)

0≤0.351.4

Missense OE?0.34 (0.26–0.45)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 6 / 9.5Missense obs/exp: 33 / 97.4Syn Z: 0.34

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 530

163 rare PASS variants

Rare truncating (LoF)

1 in 1,500

28 rare PASS variants

Rare synonymous (reference)

1 in 340

98 rare PASS variants

Rare missense and truncating variants are carried at similar rates in KRAS; this gene does not show strong loss-of-function constraint by this measure. 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 690	1 in 1,400
South Asian	~43k	1 in 530	1 in 1,200
Remaining (unassigned)	~30k	1 in 280	1 in 1,500
European (Finnish)	~27k	1 in 4,400	1 in 4,400
Admixed American	~22k	1 in 310	1 in 3,700
African / African American	~21k	1 in 710	1 in 1,500
East Asian	~20k	1 in 1,200	≈ 1 in 6,600
Ashkenazi Jewish	~13k	≈ 1 in 4,300	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 480	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

KRAS · 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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

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

Carcinoma, Pancreatic DuctalColorectal NeoplasmsCarcinoma, Non-Small-Cell Lung

A Study to Learn About the Study Medicine PF-07934040 When Given Alone or With Other Anti-cancer Therapies in People With Advanced Solid Tumors That Have a Genetic Mutation.

ACTIVE NOT RECRUITING

NCT06447662Phase PHASE1PfizerStarted 2024-06-27

PF-07934040GemcitabineNab-paclitaxel

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

KRAS Mutation-Related TumorsAdvanced Lung CancerRefractory Tumor

Trametinib Plus Anlotinib Combined With Tislelizumab in KRAS-mutant NSCLC

NOT YET RECRUITING

NCT06456138Phase PHASE1, PHASE2Shanghai Chest HospitalStarted 2024-07-01

TrametinibAnlotinibTislelizumab

Advanced Solid CancerPancreatic Ductal Adenocarcinoma (PDAC)Colorectal Adenocarcinoma

Phase 1 Study of NW-301V TCR-T Cells in Advanced Solid Tumors With KRAS G12V Mutation

NOT YET RECRUITING

NCT07875920Phase PHASE1Neowise BiotechnologyStarted 2026-10

FludarabineCyclophosphamideNW-301V

Lung AdenocarcinomaLung Non-Small Cell CarcinomaRecurrent Lung Non-Squamous Non-Small Cell Carcinoma

Testing the Use of Targeted Treatment (AMG 510) for KRAS G12C Mutated Advanced Non-squamous Non-small Cell Lung Cancer (A Lung-MAP Treatment Trial)

ACTIVE NOT RECRUITING

NCT04625647Phase PHASE2SWOG Cancer Research NetworkStarted 2021-04-16

Sotorasib

Pancreatic CancerMetastatic Pancreatic CancerMetastatic Pancreatic Adenocarcinoma

A Study to Evaluate the Effectiveness and Safety of Setidegrasib, Given With Either mFOLFIRINOX or NALIRIFOX Chemotherapies, in People With Pancreatic Cancer

RECRUITING

NCT07409272Phase PHASE3Astellas Pharma Global Development, Inc.Started 2026-02-17

SetidegrasibOxaliplatinLeucovorin

Carcinoma, Non-Small-Cell LungNeoplasm Metastasis

A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer

RECRUITING

NCT06119581Phase PHASE3Eli Lilly and CompanyStarted 2023-12-21

LY3537982PembrolizumabPlacebo

Metastatic Solid CancersColorectal CancerBreast Cancer

Autologous T-cells Genetically Engineered to Express Receptors Reactive Against KRAS Mutations in Conjunction With a Vaccine Directed Against These Antigens in Participants With Metastatic Cancer

ACTIVE NOT RECRUITING

NCT06253520Phase PHASE1National Cancer Institute (NCI)Started 2024-05-16

AldesleukinFludarabineCyclophosphamide

Colorectal Cancer MetastaticBrain Metastases, AdultRas (KRAS or NRAS) Gene Mutation

Comparison of Molecular-Genetic Concordance of the Primary Tumor and Brain Metastases of Colorectal Cancer

RECRUITING

NCT06449989Blokhin's Russian Cancer Research CenterStarted 2024-04-01

Tumor samples will be tested for mutation status of KRAS, NRAS, BRAF, HER2 and MSI

Solid TumorNon-Small-Cell Lung CancerPancreatic Ductal Adenocarcinoma

A Study to Find a Suitable Dose of ASP5834 in Adults With Solid Tumors

RECRUITING

NCT07094204Phase PHASE1Astellas Pharma IncStarted 2025-07-25