# NM_001085049.3(MRAS):c.453G>A (p.Pro151=)

https://sugi.bio/variant/mras-p-pro151

## Summary

**MRAS p.Pro151= (c.453G>A)** is classified **Benign** in MRAS (ClinVar, Expert panel, 7 submitters; last evaluated 2024-12-03). Low-frequency (popmax 1.88%, sas); Associated with RASopathy.

**At a glance:** Benign · review: Expert panel · rsID rs149904534 · 7 submitters · 1 linked condition · low-frequency (popmax 1.88%, sas)

## For patients & families {#patients}

This is a change in the MRAS gene that is classified as benign — not considered disease-causing, submitted by 7 submitters, and is linked to RASopathy.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022213/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MRAS](https://sugi.bio/atlas/gene/MRAS/) |
| Protein change (HGVS p.) | p.Pro151= |
| Coding change (HGVS c.) | c.453G>A |
| MANE Select transcript | [NM_001085049](https://www.ncbi.nlm.nih.gov/nuccore/NM_001085049) |
| dbSNP | [rs149904534](https://www.ncbi.nlm.nih.gov/snp/rs149904534/) |
| Variant type | single nucleotide variant |
| Location | chr3:138400539-138400539 (GRCh38) |
| ClinVar | [VCV496410](https://www.ncbi.nlm.nih.gov/clinvar/variation/496410/) |

**All HGVS expressions:** `NC_000003.11:g.138119381G>A`, `NC_000003.12:g.138400539G>A`, `NM_001085049.3:c.453G>A`, `NM_001252090.2:c.453G>A`, `NM_001252091.1:c.225G>A`, `NM_001252092.2:c.225G>A`, `NM_001252093.2:c.225G>A`, `NM_012219.4:c.453G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -10.356, GERP -4.21 — fast-evolving / accelerated position
- CADD: **PHRED 1.542**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for MRAS (442 scored positions, the nearest 6 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **1.88%** (sas) · FAF95 1.8% · FAF99 1.77% · 1,707/91,024 in the highest group · 3,324/1,611,978 alleles overall — low-frequency (popmax 1.88%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 1.88% | 53 |
| Middle Eastern | 1.47% | 68 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.16% | 87 |
| Remaining individuals (not grpmax-eligible) | 0.304% | 329 |
| Admixed American | 0.152% | 659 |
| European (non-Finnish) | 0.0752% | 1,330 |
| African / African-American | 0.0213% | 4,687 |
| East Asian | 0.00446% | 22,430 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,016 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**MRAS** population constraint: LOEUF 0.444, pLI 0.99089, missense-Z 2.6024. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Noonan syndrome** — Moderate (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.61, 73% of residues very-high.

**11 experimental structure(s)** (PDB): [7SD0](https://www.rcsb.org/structure/7SD0), [7TVF](https://www.rcsb.org/structure/7TVF), [7TXH](https://www.rcsb.org/structure/7TXH), [7UPI](https://www.rcsb.org/structure/7UPI), [9B4R](https://www.rcsb.org/structure/9B4R), [9B4T](https://www.rcsb.org/structure/9B4T) — incl. mutant structure 9O0P.

## What this gene does {#gene-function}

*Describes the biological roles of MRAS (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** MRAS's established molecular role includes GTPase activity. In Reactome, MRAS is annotated in disease pathway(s) including **Gain-of-function MRAS complexes activate RAF signaling**, **SHOC2 M1731 mutant abolishes MRAS complex function**.

**Disease mechanism (Reactome):** MRAS loss or alteration is curated in [Gain-of-function MRAS complexes activate RAF signaling](https://reactome.org/content/detail/R-HSA-9726842), [SHOC2 M1731 mutant abolishes MRAS complex function](https://reactome.org/content/detail/R-HSA-9726840).

### Pathways affected {#pathways}

MRAS participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Gain-of-function MRAS complexes activate RAF signaling](https://reactome.org/content/detail/R-HSA-9726842) | curated |
| ⚕ [SHOC2 M1731 mutant abolishes MRAS complex function](https://reactome.org/content/detail/R-HSA-9726840) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** GTPase activity, GTP-dependent protein binding.

**Biological process:** Ras protein signal transduction.

## Clinical significance {#significance}

**Benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-12-03.

**Submitter consensus:** conflicting (6 Benign, 1 Likely benign).

**Submission history:** 7 submissions (2017–2026); classifications have differed over time.

**ClinGen expert panel:** Benign — RASopathy VCEP (RASopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.453G>A (p.Pro151=) variant in MRAS is a synonymous variant at position 151. This variant has a filtering allele frequency of 1.748%  in the South Asian population in gnomAD v2, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1 (RASopathy VCEP specifications version 1.4; 12/3/2024)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50021 · approved 2024-12-03 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/c4b0ae99-0a60-41ae-9906-724b163297e7).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2017-07-05 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2022-01-31 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-02-12 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2020-01-02 |
| ClinGen RASopathy Variant Curation Expert Panel | Benign | reviewed by expert panel | curation | 2024-12-03 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2023-08-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |

## Associated conditions {#conditions}

[RASopathy](https://sugi.bio/atlas/disease/rasopathy/).

**Reported phenotype names (ClinVar):** RASopathy, not provided, Inborn genetic diseases, MRAS-related disorder, not specified, AllHighlyPenetrant, Noonan spectrum disorder, rasopathies, MRAS-related condition, none provided.

## Similar variants {#similar}

Related MRAS variant pages (same residue, condition, or type): [MRAS p.Pro151Leu](/variant/mras-p-pro151leu), [MRAS p.Gln71Arg](/variant/mras-p-gln71arg), [MRAS p.Gly23Arg](/variant/mras-p-gly23arg), [MRAS p.Gly23Val](/variant/mras-p-gly23val), [MRAS p.Thr68Ile](/variant/mras-p-thr68ile), [MRAS p.Gln59=](/variant/mras-p-gln59), [MRAS c.528-2del](/variant/mras-c-528-minus-2del), [MRAS p.Ala167Gly](/variant/mras-p-ala167gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 496410). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*