# NM_004985.5(KRAS):c.101C>T (p.Pro34Leu)

https://sugi.bio/variant/kras-p-pro34leu

## Summary

**KRAS p.Pro34Leu (c.101C>T)** is classified **Pathogenic** in KRAS (ClinVar, Expert panel, 9 submitters; last evaluated 2024-09-17). AlphaMissense: likely pathogenic (0.9976); Absent from gnomAD v4.1; Associated with Noonan syndrome.

**At a glance:** Pathogenic · review: Expert panel · rsID rs104894366 · 9 submitters · 4 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the KRAS gene that is considered disease-causing, submitted by 9 submitters, and is linked to Noonan syndrome.

*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 | 27 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010955/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.Pro34Leu |
| Coding change (HGVS c.) | c.101C>T |
| MANE Select transcript | [NM_004985](https://www.ncbi.nlm.nih.gov/nuccore/NM_004985) |
| dbSNP | [rs104894366](https://www.ncbi.nlm.nih.gov/snp/rs104894366/) |
| Variant type | single nucleotide variant |
| Location | chr12:25245284-25245284 (GRCh38) |
| ClinVar | [VCV40454](https://www.ncbi.nlm.nih.gov/clinvar/variation/40454/) |

**All HGVS expressions:** `LRG_344:g.10720C>T`, `LRG_344t1:c.101C>T`, `LRG_344t2:c.101C>T`, `NC_000012.11:g.25398218G>A`, `NC_000012.12:g.25245284G>A`, `NG_007524.2:g.10720C>T`, `NM_001369786.1:c.101C>T`, `NM_001369787.1:c.101C>T`, `NM_004985.5:c.101C>T`, `NM_033360.4:c.101C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9976) — concordant with the pathogenic call
- REVEL 0.867 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.064 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.891, GERP 1.89, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 31.0**. 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.*
- Regional missense constraint: **o/e 0.30** across the covering region of the MANE Select transcript (25,225,715–25,245,384), spanning 19,669 bp — the region is depleted of missense variation. Chi-square p 1.6e-16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **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 **34** lies in a UniProt-annotated variant site (in ns3; characterized by a defective gtpase-activating protein sensitivity and a strongly reduced interaction with effectors); a UniProt-annotated variant site (in ns3); a UniProt-annotated variant site (in cfc2; characterized by a defective gtpase-activating protein sensitivity and a strongly reduced interaction with effectors); an α-helix.

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}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-09-17.

**Submitter consensus:** unanimous (9/9 Pathogenic).

**Submission history:** 9 submissions (2013–2025); classifications have been stable.

**ClinGen expert panel:** Pathogenic — RASopathy VCEP (Noonan syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PS2_VeryStrong`, `PM2_Supporting`, `PS3_Supporting`, `PS4_Moderate`, `PP2`, `PP3`, `PM5`.
*Considered but not met:* `BS1`, `BP4`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.101C>T variant in the KRAS gene is a missense variant predicted to cause substitution of proline by leucine at amino acid 34 (p.Pro34Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.867 supporting a deleterious impact to KRAS function (PP3). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). A different pathogenic missense variant has been previously identified at this codon of KRAS (c.101C>G (p.Pro34Arg)) which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 12590). This variant has been reported in 3 individuals as two confirmed de novo occurrences and one unconfirmed de novo occurrence with clinical features of a RASopathy (PS4_Moderate, PS2_VeryStrong; PMIDs: 17056636, 30732632, ClinVar SCV: SCV000207884.10, Internal lab contributors: GeneDx). A RAS activation assay showed that this variant led to increased RAS activation (PS3_Supporting; PMID: 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4_Moderate, PM5, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 09/17/2024)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50021 · approved 2024-09-17 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/bf62d2f1-6047-4d6b-9cb9-dfdab291cdfb).*
*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 |
| --- | --- | --- | --- | --- |
| Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Pathogenic | no assertion criteria provided | clinical testing | 2015-01-15 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2013-06-04 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-23 |
| Molecular Genetics, Centre for Human Genetics | Pathogenic | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-16 |
| Variantyx, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-27 |
| ClinGen RASopathy Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2024-09-17 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-25 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-19 |

## Associated conditions {#conditions}

[Noonan syndrome](https://sugi.bio/atlas/disease/noonan-syndrome/), [Noonan syndrome 1](https://sugi.bio/atlas/disease/noonan-syndrome-1/), [Noonan syndrome 3](https://sugi.bio/atlas/disease/noonan-syndrome-3/), [RASopathy](https://sugi.bio/atlas/disease/rasopathy/).

**Reported phenotype names (ClinVar):** Noonan syndrome, not provided, RASopathy, Noonan syndrome 1, Noonan syndrome 3, Cardiovascular phenotype, none provided, Noonan spectrum disorder, rasopathies, Noonan's syndrome.

## Same-residue context {#hotspot}

Residue **34** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [KRAS p.Pro34Arg](/variant/kras-p-pro34arg), [KRAS p.Pro34Gln](/variant/kras-p-pro34gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related KRAS variant pages (same residue, condition, or type): [KRAS p.Pro34Arg](/variant/kras-p-pro34arg), [KRAS p.Pro34Gln](/variant/kras-p-pro34gln), [KRAS p.Pro34=](/variant/kras-p-pro34), [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.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 40454). 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.*