# NM_058195.4(CDKN2A):c.139C>G (p.Leu47Val)

https://sugi.bio/variant/cdkn2a-p-leu47val

## Summary

**CDKN2A p.Leu47Val (c.139C>G)** is classified **Uncertain significance** in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CDKN2A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to hereditary neoplastic 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 | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDKN2A](https://sugi.bio/atlas/gene/CDKN2A/) |
| Protein change (HGVS p.) | p.Leu47Val |
| Coding change (HGVS c.) | c.139C>G |
| MANE Select transcript | [NM_000077](https://www.ncbi.nlm.nih.gov/nuccore/NM_000077) (variant reported on NM_058195) |
| Variant type | single nucleotide variant |
| Location | chr9:21994193-21994193 (GRCh38) |
| ClinVar | [VCV4633820](https://www.ncbi.nlm.nih.gov/clinvar/variation/4633820/) |

**All HGVS expressions:** `LRG_11:g.5299C>G`, `LRG_11t2:c.139C>G`, `NC_000009.11:g.21994192G>C`, `NC_000009.12:g.21994193G>C`, `NG_007485.1:g.5299C>G`, `NM_001363763.2:c.-4+628C>G`, `NM_058195.4:c.139C>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 2.207, GERP -1.6, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.9**. 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: **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}

**CDKN2A** population constraint: LOEUF 0.791, pLI 0.61783, missense-Z -1.3314; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **melanoma-pancreatic cancer syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **47** lies in the 'interaction with cdk5rap3 and mdm2' region.

AlphaFold model confidence (whole protein): pLDDT 77.02, 1% of residues very-high.

**5 experimental structure(s)** (PDB): [1A5E](https://www.rcsb.org/structure/1A5E), [1BI7](https://www.rcsb.org/structure/1BI7), [1DC2](https://www.rcsb.org/structure/1DC2), [2A5E](https://www.rcsb.org/structure/2A5E), [7OZT](https://www.rcsb.org/structure/7OZT) — incl. mutant structure 7OZT.

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

*Describes the biological roles of CDKN2A (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:** CDKN2A's established molecular role includes RNA binding. p.Leu47Val falls in the interaction with cdk5rap3 and mdm2 region. In Reactome, CDKN2A is annotated in disease pathway(s) including **Defective Intrinsic Pathway for Apoptosis Due to p14ARF Loss of Function**, **Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4**.

**Disease mechanism (Reactome):** CDKN2A loss or alteration is curated in [Defective Intrinsic Pathway for Apoptosis Due to p14ARF Loss of Function](https://reactome.org/content/detail/R-HSA-9645722), [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4](https://reactome.org/content/detail/R-HSA-9630791), [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6](https://reactome.org/content/detail/R-HSA-9630794).

### Pathways affected {#pathways}

CDKN2A participates in **20 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective Intrinsic Pathway for Apoptosis Due to p14ARF Loss of Function](https://reactome.org/content/detail/R-HSA-9645722) | curated |
| ⚕ [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4](https://reactome.org/content/detail/R-HSA-9630791) | curated |
| ⚕ [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6](https://reactome.org/content/detail/R-HSA-9630794) | curated |
| ⚕ [Evasion of Oncogene Induced Senescence Due to p14ARF Defects](https://reactome.org/content/detail/R-HSA-9646303) | curated |
| ⚕ [Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4](https://reactome.org/content/detail/R-HSA-9632697) | curated |
| ⚕ [Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6](https://reactome.org/content/detail/R-HSA-9632700) | curated |
| ⚕ [Evasion of Oxidative Stress Induced Senescence Due to p14ARF Defects](https://reactome.org/content/detail/R-HSA-9646304) | curated |
| [Apoptotic factor-mediated response](https://reactome.org/content/detail/R-HSA-111471) | curated |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [Nuclear events mediated by NFE2L2](https://reactome.org/content/detail/R-HSA-9759194) | curated |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [Regulation of MITF-M-dependent genes involved in cell cycle and proliferation](https://reactome.org/content/detail/R-HSA-9825892) | curated |
| [Regulation of RUNX3 expression and activity](https://reactome.org/content/detail/R-HSA-8941858) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |
| [SUMOylation of transcription factors](https://reactome.org/content/detail/R-HSA-3232118) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [Stabilization of p53](https://reactome.org/content/detail/R-HSA-69541) | curated |
| [Transcriptional Regulation by VENTX](https://reactome.org/content/detail/R-HSA-8853884) | curated |

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

**Molecular function:** RNA binding, cyclin-dependent protein serine/threonine kinase inhibitor activity, protein kinase binding, NF-kappaB binding, p53 binding, SUMO transferase activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, negative regulation of cell-matrix adhesion, Ras protein signal transduction, negative regulation of cell population proliferation, negative regulation of cell growth, negative regulation of cyclin-dependent protein serine/threonine kinase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-02.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-02 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Tumor predisposition, Neoplastic Syndromes, Hereditary.

## Similar variants {#similar}

Related CDKN2A variant pages (same residue, condition, or type): [CDKN2A p.Leu47Pro](/variant/cdkn2a-p-leu47pro), [CDKN2A p.Arg47=](/variant/cdkn2a-p-arg47), [CDKN2A p.Arg47Lys](/variant/cdkn2a-p-arg47lys), [CDKN2A p.Leu47=](/variant/cdkn2a-p-leu47), [CDKN2A c.150+2T>G](/variant/cdkn2a-c-150-plus-2t-g), [CDKN2A c.151-1G>C](/variant/cdkn2a-c-151-minus-1g-c), [CDKN2A c.151-1G>T](/variant/cdkn2a-c-151-minus-1g-t), [CDKN2A c.151-2A>G](/variant/cdkn2a-c-151-minus-2a-g).

### 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 4633820). 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.*