MRAS

Chr 3AD

muscle RAS oncogene homolog

Also known as: M-RAs, NS11, R-RAS3, RRAS3

NCBI Gene: 22808 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the Ras family of small GTPases. These membrane-associated proteins function as signal transducers in multiple processes including cell growth and differentiation, and dysregulation of Ras signaling has been associated with many types of cancer. The encoded protein may play a role in the tumor necrosis factor-alpha and MAP kinase signaling pathways. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 121 VUS of 267 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MRAS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.00 (0.00–0.37)

0≤0.351.4

Missense OE?0.43 (0.34–0.53)

0≤0.61.4

Synonymous OE?0.89

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

This gene — mechanism propensity

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.1

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

References

1.PMID 29311130 ↗

ClinVar Variant Classifications

267 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic5

VUS121

Likely Benign121

Benign11

Conflicting4

Likely Pathogenic

121

VUS

121

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	5	0	0	5
VUS	7	105	9	0	121
Likely Benign	0	0	43	78	121
Benign	1	0	8	2	11
Conflicting	—				4
Total	8	110	60	80	262

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap MRAS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →