# NM_004985.5(KRAS):c.24A>G (p.Val8=)

https://sugi.bio/variant/kras-p-val8

## Summary

**KRAS p.Val8= (c.24A>G)** is classified **Likely benign** in KRAS (ClinVar, Expert panel, 16 submitters; last evaluated 2017-04-18). Ultra-rare (popmax 0.0604%, nfe); Associated with RASopathy.

**At a glance:** Likely benign · review: Expert panel · rsID rs147406419 · 16 submitters · 13 linked conditions · ultra-rare (popmax 0.0604%, nfe)

## For patients & families {#patients}

This is a change in the KRAS gene that is classified as likely benign — not considered disease-causing, submitted by 16 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 | [KRAS](https://sugi.bio/atlas/gene/KRAS/) |
| Protein change (HGVS p.) | p.Val8= |
| Coding change (HGVS c.) | c.24A>G |
| MANE Select transcript | [NM_004985](https://www.ncbi.nlm.nih.gov/nuccore/NM_004985) |
| dbSNP | [rs147406419](https://www.ncbi.nlm.nih.gov/snp/rs147406419/) |
| Variant type | single nucleotide variant |
| Location | chr12:25245361-25245361 (GRCh38) |
| ClinVar | [VCV45119](https://www.ncbi.nlm.nih.gov/clinvar/variation/45119/) |

**All HGVS expressions:** `LRG_344:g.10643A>G`, `LRG_344t1:c.24A>G`, `LRG_344t2:c.24A>G`, `NC_000012.11:g.25398295T>C`, `NC_000012.12:g.25245361T>C`, `NG_007524.2:g.10643A>G`, `NM_001369786.1:c.24A>G`, `NM_001369787.1:c.24A>G`, `NM_004985.5:c.24A>G`, `NM_033360.4:c.24A>G`

## 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 2.358, GERP -0.518, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.232**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0604%** (nfe) · FAF95 0.0566% · FAF99 0.0552% · 712/1,179,132 in the highest group · 742/1,612,464 alleles overall — ultra-rare (popmax 0.0604%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0604% | 1,656 |
| Remaining individuals (not grpmax-eligible) | 0.0369% | 2,713 |
| African / African-American | 0.00667% | 14,986 |
| Admixed American | 0.00167% | 59,894 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,990 |

*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}

**KRAS** population constraint: LOEUF 0.264, pLI 0.99914, missense-Z 3.0903. *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):

- **cardiofaciocutaneous syndrome** — Strong (AD)
- **Noonan syndrome** — Definitive (AD)
- **Costello syndrome** — Disputed (AD)

## Protein context {#protein}

Residue **8** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 91.65, 78% of residues very-high.

**549 experimental structure(s)** (PDB): [1D8D](https://www.rcsb.org/structure/1D8D), [1D8E](https://www.rcsb.org/structure/1D8E), [1KZO](https://www.rcsb.org/structure/1KZO), [1KZP](https://www.rcsb.org/structure/1KZP), [1N4P](https://www.rcsb.org/structure/1N4P), [1N4Q](https://www.rcsb.org/structure/1N4Q) — incl. mutant structure 4LDJ.

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

*Describes the biological roles of KRAS (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:** KRAS's established molecular role includes GTPase activity. In Reactome, KRAS is annotated in disease pathway(s) including **Paradoxical activation of RAF signaling by kinase inactive BRAF**, **Signaling by RAS GAP mutants**.

**Disease mechanism (Reactome):** KRAS loss or alteration is curated in [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [Signaling by RAS GAP mutants](https://reactome.org/content/detail/R-HSA-9753510), [Signaling by RAS GTPase mutants](https://reactome.org/content/detail/R-HSA-9753512).

### Pathways affected {#pathways}

KRAS participates in **71 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by RAS GAP mutants](https://reactome.org/content/detail/R-HSA-9753510) | curated |
| ⚕ [Signaling by RAS GTPase mutants](https://reactome.org/content/detail/R-HSA-9753512) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| ⚕ [Constitutive Signaling by EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810) | other |
| ⚕ [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382) | other |
| ⚕ [Constitutive Signaling by Overexpressed ERBB2](https://reactome.org/content/detail/R-HSA-9634285) | other |
| ⚕ [RAS signaling downstream of NF1 loss-of-function variants](https://reactome.org/content/detail/R-HSA-6802953) | other |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | other |
| ⚕ [Signaling by ERBB2 ECD mutants](https://reactome.org/content/detail/R-HSA-9665348) | other |
| ⚕ [Signaling by ERBB2 KD Mutants](https://reactome.org/content/detail/R-HSA-9664565) | other |
| ⚕ [Signaling by ERBB2 TMD/JMD mutants](https://reactome.org/content/detail/R-HSA-9665686) | other |
| ⚕ [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302) | other |
| ⚕ [Signaling by FGFR2 in disease](https://reactome.org/content/detail/R-HSA-5655253) | other |
| ⚕ [Signaling by FGFR3 in disease](https://reactome.org/content/detail/R-HSA-5655332) | other |
| ⚕ [Signaling by FGFR4 in disease](https://reactome.org/content/detail/R-HSA-5655291) | other |
| ⚕ [Signaling by FLT3 ITD and TKD mutants](https://reactome.org/content/detail/R-HSA-9703648) | other |
| ⚕ [Signaling by FLT3 fusion proteins](https://reactome.org/content/detail/R-HSA-9703465) | other |
| ⚕ [Signaling by PDGFRA extracellular domain mutants](https://reactome.org/content/detail/R-HSA-9673770) | other |
| ⚕ [Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants](https://reactome.org/content/detail/R-HSA-9673767) | other |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | other |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | other |
| ⚕ [Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants](https://reactome.org/content/detail/R-HSA-9670439) | other |
| [RAS processing](https://reactome.org/content/detail/R-HSA-9648002) | curated |
| [RUNX3 regulates p14-ARF](https://reactome.org/content/detail/R-HSA-8951936) | curated |
| [Signaling by CSF3 (G-CSF)](https://reactome.org/content/detail/R-HSA-9674555) | curated |
| [Activated NTRK2 signals through FRS2 and FRS3](https://reactome.org/content/detail/R-HSA-9028731) | other |
| [Activated NTRK2 signals through RAS](https://reactome.org/content/detail/R-HSA-9026519) | other |
| [Activated NTRK3 signals through RAS](https://reactome.org/content/detail/R-HSA-9034864) | other |
| [Activation of RAS in B cells](https://reactome.org/content/detail/R-HSA-1169092) | other |
| [CD209 (DC-SIGN) signaling](https://reactome.org/content/detail/R-HSA-5621575) | other |
| [Ca2+ pathway](https://reactome.org/content/detail/R-HSA-4086398) | other |
| [DAP12 signaling](https://reactome.org/content/detail/R-HSA-2424491) | other |
| [Downstream signal transduction](https://reactome.org/content/detail/R-HSA-186763) | other |
| [EGFR Transactivation by Gastrin](https://reactome.org/content/detail/R-HSA-2179392) | other |
| [Erythropoietin activates RAS](https://reactome.org/content/detail/R-HSA-9027284) | other |
| [Estrogen-stimulated signaling through PRKCZ](https://reactome.org/content/detail/R-HSA-9634635) | other |
| [FCERI mediated MAPK activation](https://reactome.org/content/detail/R-HSA-2871796) | other |
| [FLT3 Signaling](https://reactome.org/content/detail/R-HSA-9607240) | other |
| [FRS-mediated FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5654693) | other |
| [FRS-mediated FGFR2 signaling](https://reactome.org/content/detail/R-HSA-5654700) | other |
| [FRS-mediated FGFR3 signaling](https://reactome.org/content/detail/R-HSA-5654706) | other |
| [FRS-mediated FGFR4 signaling](https://reactome.org/content/detail/R-HSA-5654712) | other |
| [GRB2 events in EGFR signaling](https://reactome.org/content/detail/R-HSA-179812) | other |
| [GRB2 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963640) | other |
| [Insulin receptor signalling cascade](https://reactome.org/content/detail/R-HSA-74751) | other |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | other |
| [MET activates RAS signaling](https://reactome.org/content/detail/R-HSA-8851805) | other |
| [NCAM signaling for neurite out-growth](https://reactome.org/content/detail/R-HSA-375165) | other |
| [Negative regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5675221) | other |
| [PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases](https://reactome.org/content/detail/R-HSA-8849471) | other |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | other |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | other |
| [Ras activation upon Ca2+ influx through NMDA receptor](https://reactome.org/content/detail/R-HSA-442982) | other |
| [Regulation of RAS by GAPs](https://reactome.org/content/detail/R-HSA-5658442) | other |
| [SHC-mediated cascade:FGFR1](https://reactome.org/content/detail/R-HSA-5654688) | other |
| [SHC-mediated cascade:FGFR2](https://reactome.org/content/detail/R-HSA-5654699) | other |
| [SHC-mediated cascade:FGFR3](https://reactome.org/content/detail/R-HSA-5654704) | other |
| [SHC-mediated cascade:FGFR4](https://reactome.org/content/detail/R-HSA-5654719) | other |
| [SHC-related events triggered by IGF1R](https://reactome.org/content/detail/R-HSA-2428933) | other |
| [SHC1 events in EGFR signaling](https://reactome.org/content/detail/R-HSA-180336) | other |
| [SHC1 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1250196) | other |
| [SHC1 events in ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1250347) | other |
| [SOS-mediated signalling](https://reactome.org/content/detail/R-HSA-112412) | other |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | electronic |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | other |
| [Signalling to RAS](https://reactome.org/content/detail/R-HSA-167044) | other |
| [Tie2 Signaling](https://reactome.org/content/detail/R-HSA-210993) | other |
| [VEGFR2 mediated cell proliferation](https://reactome.org/content/detail/R-HSA-5218921) | other |
| [p38MAPK events](https://reactome.org/content/detail/R-HSA-171007) | other |

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

**Molecular function:** GTPase activity, identical protein binding, protein-containing complex binding.

**Biological process:** positive regulation of gene expression.

## Clinical significance {#significance}

**Likely benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2017-04-18.

**Submitter consensus:** conflicting (13 Likely benign, 3 Benign).

**Submission history:** 16 submissions (2010–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — RASopathy VCEP (RASopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The filtering allele frequency of the c.24A>G (p.Val8=) variant in the KRAS gene is 0.0499% (35/51828) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50021 · approved 2017-04-18 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/56c9c209-4dc1-4b23-8b13-5e4465526b77).*
*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 |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| ClinGen RASopathy Variant Curation Expert Panel | Likely benign | reviewed by expert panel | curation | 2017-04-18 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2014-05-23 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2010-02-24 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-23 |
| Clinical Genetics, Academic Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2021-12-30 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | no assertion criteria provided | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-08-26 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-29 |

## Associated conditions {#conditions}

[RASopathy](https://sugi.bio/atlas/disease/rasopathy/), [gastric cancer](https://sugi.bio/atlas/disease/gastric-cancer/), [urinary bladder cancer](https://sugi.bio/atlas/disease/urinary-bladder-cancer/), [exocrine pancreatic carcinoma](https://sugi.bio/atlas/disease/exocrine-pancreatic-carcinoma/), [arteriovenous malformations of the brain](https://sugi.bio/atlas/disease/arteriovenous-malformations-of-the-brain/), [linear nevus sebaceous syndrome](https://sugi.bio/atlas/disease/linear-nevus-sebaceous-syndrome/), [lung cancer](https://sugi.bio/atlas/disease/lung-cancer/), [Toriello-Lacassie-Droste syndrome](https://sugi.bio/atlas/disease/toriello-lacassie-droste-syndrome/), [Noonan syndrome 3](https://sugi.bio/atlas/disease/noonan-syndrome-3/), [autoimmune lymphoproliferative syndrome type 4](https://sugi.bio/atlas/disease/autoimmune-lymphoproliferative-syndrome-type-4/), [cardiofaciocutaneous syndrome 2](https://sugi.bio/atlas/disease/cardiofaciocutaneous-syndrome-2/), [hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/), [acute myeloid leukemia](https://sugi.bio/atlas/disease/acute-myeloid-leukemia/).

**Reported phenotype names (ClinVar):** RASopathy, not specified, not provided, Cardiovascular phenotype, Acute myeloid leukemia, Autoimmune lymphoproliferative syndrome type 4, Carcinoma of pancreas, Cardiofaciocutaneous syndrome 2, Cerebral arteriovenous malformation, Familial cancer of breast.

## Similar variants {#similar}

Related KRAS variant pages (same residue, condition, or type): [KRAS p.Val8Ile](/variant/kras-p-val8ile), [KRAS p.Asp153Val](/variant/kras-p-asp153val), [KRAS p.Gln22Arg](/variant/kras-p-gln22arg), [KRAS p.Gly60Arg](/variant/kras-p-gly60arg), [KRAS p.Lys5Asn](/variant/kras-p-lys5asn), [KRAS p.Pro34Leu](/variant/kras-p-pro34leu), [KRAS p.Ser65Ile](/variant/kras-p-ser65ile), [KRAS p.Thr58Ile](/variant/kras-p-thr58ile).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 45119). 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.*