# NM_004985.5(KRAS):c.21G>A (p.Val7=)

https://sugi.bio/variant/kras-p-val7

## Summary

**KRAS p.Val7= (c.21G>A)** is classified **Likely benign** in KRAS (ClinVar, Single submitter, 2 submitters; last evaluated 2024-12-29). Absent from gnomAD v4.1; Associated with RASopathy.

**At a glance:** Likely benign · review: Single submitter · 2 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the KRAS gene that is classified as likely benign — not considered disease-causing, submitted by 2 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.Val7= |
| Coding change (HGVS c.) | c.21G>A |
| MANE Select transcript | [NM_004985](https://www.ncbi.nlm.nih.gov/nuccore/NM_004985) |
| Variant type | single nucleotide variant |
| Location | chr12:25245364-25245364 (GRCh38) |
| ClinVar | [VCV3236463](https://www.ncbi.nlm.nih.gov/clinvar/variation/3236463/) |

**All HGVS expressions:** `LRG_344:g.10640G>A`, `LRG_344t1:c.21G>A`, `LRG_344t2:c.21G>A`, `NC_000012.11:g.25398298C>T`, `NC_000012.12:g.25245364C>T`, `NG_007524.2:g.10640G>A`, `NM_001369786.1:c.21G>A`, `NM_001369787.1:c.21G>A`, `NM_004985.5:c.21G>A`, `NM_033360.4:c.21G>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 4.025, GERP 1.89, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.96**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.66 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **7** 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-29.

**Submitter consensus:** unanimous (1/1 Likely benign).

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Adnan Lab, Aga Khan University |  | no assertion criteria provided | research |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-29 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** RASopathy, Pancreatic ductal adenocarcinoma, Noonan spectrum disorder, rasopathies.

## Same-residue context {#hotspot}

Residue **7** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [KRAS p.Val7Glu](/variant/kras-p-val7glu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related KRAS variant pages (same residue, condition, or type): [KRAS p.Val7Glu](/variant/kras-p-val7glu), [KRAS p.Val7Met](/variant/kras-p-val7met), [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).

### 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 3236463). 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.*