MRAS

Chr 3AD

muscle RAS oncogene homolog

ENSG00000158186 UniProt: O14807 OMIM: 608435

The protein is a small GTPase that functions as a signal transducer in the Ras-MAPK signaling pathway, forming part of the SHOC2-MRAS-PP1c complex that regulates RAF kinase activation and controls cell proliferation and survival. Mutations cause Noonan syndrome 11 with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.92, LOEUF 0.37), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

GOFmechanismADLOEUF 0.371 OMIM phenotype

VCEP Guidelines: RASopathyReleased

View Specifications ClinGen Panel

Clinical Summary— MRAS

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Gene-Disease Validity (ClinGen)

Noonan syndrome · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

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

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.37LOEUF

pLI 0.921

Z-score 2.64

OE 0.00 (0.00–0.37)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

2.33Z-score

OE missense 0.43 (0.34–0.53)

56 obs / 130.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.37)

0≤0.351.4

Missense OE0.43 (0.34–0.53)

0≤0.61.4

Synonymous OE0.89

0≤1.21.6

LoF obs/exp: 0 / 8.1Missense obs/exp: 56 / 130.9Syn Z: 0.59

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMRAS-related Noonan syndromeGOFAD

0.6163th %ile

GOF

0.6638th %ile

LOF

0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function 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

LOFLOEUF 0.37

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

GOFActivating mutations in MRAS (as well as SHOC2 and PP1) do occur in the RASopathy Noonan syndrome, underscoring a key role for MRAS within the RAS-ERK pathway.PMID:29311130

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.