NRAS

Chr 1AD

NRAS proto-oncogene, GTPase

NCBI Gene: 4893 ENSG00000213281 UniProt: P01111

Ras proteins bind GDP/GTP and possess intrinsic GTPase activity

Primary Disease Associations & Inheritance

?RAS-associated autoimmune lymphoproliferative syndrome type IV, somaticMIM #614470

Colorectal cancer, somaticMIM #114500

Epidermal nevus, somaticMIM #162900

Melanocytic nevus syndrome, congenital, somaticMIM #137550

Neurocutaneous melanosis, somaticMIM #249400

Noonan syndrome 6MIM #613224

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

ClinVar variants

Pathogenic / LP

0.49

pLI score

Active trials

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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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.

0.61LOEUF

pLI 0.490

Z-score 2.39

OE 0.19 (0.08–0.61)

Tolerant

Typical tolerance to LoF variation

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.

1.71Z-score

OE missense 0.53 (0.42–0.66)

55 obs / 104.2 exp

Tolerant

Mild missense constraint

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.0.19 (0.08–0.61)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.53 (0.42–0.66)

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.1.00

0≤1.21.6

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

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.

Gene2Phenotype Curations

NRAS-related Noonan syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. Disorders

G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

NRAS PROTOONCOGENE, GTPase; NRAS

MIM #164790 · *

?RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic

MIM #614470