KRAS

Chr 12AD

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

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]

Primary Disease Associations & Inheritance

Arteriovenous malformation of the brain, somaticMIM #108010

Bladder cancer, somaticMIM #109800

Breast cancer, somaticMIM #114480

Cardiofaciocutaneous syndrome 2MIM #615278

Gastric cancer, somaticMIM #613659

Leukemia, acute myeloid, somaticMIM #601626

Lung cancer, somaticMIM #211980

Noonan syndrome 3MIM #609942

Oculoectodermal syndrome, somaticMIM #600268

Pancreatic carcinoma, somaticMIM #260350

RAS-associated autoimmune leukoproliferative disorderMIM #614470

Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaicMIM #163200

UniProtLeukemia, juvenile myelomonocytic

382

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— KRAS

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Gene-Disease Validity (ClinGen)

cardiofaciocutaneous syndrome · ADStrong

Strong evidence — appropriate for clinical testing

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

72 Pathogenic / Likely Pathogenic· 120 VUS of 382 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.63 (0.34–1.24)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.34 (0.26–0.45)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93

0≤1.21.6

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

ClinVar Variant Classifications

382 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37

Likely Pathogenic35

VUS120

Likely Benign144

Benign28

Conflicting18

Pathogenic

Likely Pathogenic

120

VUS

144

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	11	26	0	37
Likely Pathogenic	0	26	9	0	35
VUS	3	89	24	4	120
Likely Benign	0	1	73	70	144
Benign	0	0	27	1	28
Conflicting	—				18
Total	3	127	159	75	382

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

View in 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.

Gene2Phenotype Curations

KRAS-related cardiofaciocutaneous syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkin

G2P ↗

KRAS-related Noonan syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkin

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

KRAS PROTOONCOGENE, GTPase; KRAS

MIM #190070 · *

Arteriovenous malformation of the brain, somatic

MIM #108010