# NM_000077.5(CDKN2A):c.356_363del (p.Glu119fs)

https://sugi.bio/variant/cdkn2a-p-glu119fs

## Summary

**CDKN2A p.Glu119fs (c.356_363del)** is classified **Pathogenic** in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-28). Associated with familial melanoma.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CDKN2A gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to familial melanoma.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Multigenic/multifactorial |
| Age of onset (of this condition) | Adult |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CDKN2A is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Familial melanoma** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Melanoma — Very frequent (99-80%)
- Nevus — Very frequent (99-80%)
- Dry skin — Frequent (79-30%)
- Freckling — Frequent (79-30%)
- Abnormality of the hair — Frequent (79-30%)
- Abnormality of the lymphatic system — Frequent (79-30%)
- Retinopathy — Occasional (29-5%)
- Abnormality of extrapyramidal motor function — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003460/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.Glu119fs |
| Coding change (HGVS c.) | c.356_363del |
| MANE Select transcript | [NM_000077](https://www.ncbi.nlm.nih.gov/nuccore/NM_000077) |
| Variant type | Deletion |
| Location | chr9:21970996-21971003 (GRCh38) |
| ClinVar | [VCV3648010](https://www.ncbi.nlm.nih.gov/clinvar/variation/3648010/) |

**All HGVS expressions:** `LRG_11:g.28489_28496del`, `LRG_11t1:c.352_359del`, `LRG_11t2:c.395_*3del`, `NC_000009.11:g.21970999_21971006del`, `NC_000009.12:g.21971000_21971007del`, `NG_007485.1:g.28489_28496del`, `NM_000077.6:c.352_359delGCTGAGGA`, `NM_001195132.2:c.356_363del`, `NM_001363763.2:c.203_210del`, `NM_058195.4:c.399_*7del`, `NM_058197.5:c.*279_*286del`

## Computational & population evidence {#evidence}

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

- **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 5.821, GERP 1.09, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 3**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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 **119** lies in an α-helix; a UniProt-annotated variant site (in a biliary tract tumor); the 'disordered' 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.Glu119fs falls in the disordered 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-28.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-28 |

## Associated conditions {#conditions}

[familial melanoma](https://sugi.bio/atlas/disease/familial-melanoma/).

**Reported phenotype names (ClinVar):** Familial melanoma, Hereditary melanoma, Hereditary cutaneous melanoma.

## Similar variants {#similar}

Related CDKN2A variant pages (same residue, condition, or type): [CDKN2A p.Glu119Lys](/variant/cdkn2a-p-glu119lys), [CDKN2A c.193+1del](/variant/cdkn2a-c-193-plus-1del), [CDKN2A c.457+1_457+10del](/variant/cdkn2a-c-457-plus-1-457-plus-10del), [CDKN2A p.Ala76fs](/variant/cdkn2a-p-ala76fs), [CDKN2A p.Glu120fs](/variant/cdkn2a-p-glu120fs), [CDKN2A p.His123fs](/variant/cdkn2a-p-his123fs), [CDKN2A p.Leu32_Leu37del](/variant/cdkn2a-p-leu32-leu37del), [CDKN2A p.Leu64fs](/variant/cdkn2a-p-leu64fs).

### 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 3648010). 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.*