# NM_002228.4(JUN):c.659del (p.Pro220fs)

https://sugi.bio/variant/jun-p-pro220fs

## Summary

**JUN p.Pro220fs (c.659del)** is classified **Pathogenic** in JUN (ClinVar, No assertion criteria, 1 submitter). No gnomAD frequency available for this variant; Associated with breast neoplasm.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs2524557470 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

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

*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 | 1202 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [JUN](https://sugi.bio/atlas/gene/JUN/) |
| Protein change (HGVS p.) | p.Pro220fs |
| Coding change (HGVS c.) | c.659del |
| MANE Select transcript | [NM_002228](https://www.ncbi.nlm.nih.gov/nuccore/NM_002228) |
| dbSNP | [rs2524557470](https://www.ncbi.nlm.nih.gov/snp/rs2524557470/) |
| Variant type | Deletion |
| Location | chr1:58782412-58782412 (GRCh38) |
| ClinVar | [VCV1706623](https://www.ncbi.nlm.nih.gov/clinvar/variation/1706623/) |

**All HGVS expressions:** `NC_000001.10:g.59248086del`, `NC_000001.11:g.58782414del`, `NG_047027.2:g.6635del`, `NM_002228.4:c.659del`, `NM_002228.4:c.659delC`

## 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 -0.804, GERP -1.07, phastCons 0.004 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.716, pLI 0.4676. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (1 of 1)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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.
- Repeat context: **simple_repeat** ((CTG)n). The alignment of this deletion is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**JUN** population constraint: LOEUF 0.716, pLI 0.4676, missense-Z 1.2855. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **220** lies in the 'interaction with page4' region.

AlphaFold model confidence (whole protein): pLDDT 62.45, 22% of residues very-high.

**10 experimental structure(s)** (PDB): [1A02](https://www.rcsb.org/structure/1A02), [1FOS](https://www.rcsb.org/structure/1FOS), [1JNM](https://www.rcsb.org/structure/1JNM), [1JUN](https://www.rcsb.org/structure/1JUN), [1S9K](https://www.rcsb.org/structure/1S9K), [1T2K](https://www.rcsb.org/structure/1T2K).

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

*Describes the biological roles of JUN (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:** JUN's established molecular role includes transcription cis-regulatory region binding. p.Pro220fs falls in the interaction with page4 region. In Reactome, JUN is annotated in disease pathway(s) including **Signaling by ALK fusions and activated point mutants**, **WNT5:FZD7-mediated leishmania damping**.

**Disease mechanism (Reactome):** JUN loss or alteration is curated in [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370), [WNT5:FZD7-mediated leishmania damping](https://reactome.org/content/detail/R-HSA-9673324), [Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models](https://reactome.org/content/detail/R-HSA-8862803).

### Pathways affected {#pathways}

JUN participates in **15 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| ⚕ [WNT5:FZD7-mediated leishmania damping](https://reactome.org/content/detail/R-HSA-9673324) | curated |
| ⚕ [Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models](https://reactome.org/content/detail/R-HSA-8862803) | electronic |
| [Activation of the AP-1 family of transcription factors](https://reactome.org/content/detail/R-HSA-450341) | curated |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [FCERI mediated MAPK activation](https://reactome.org/content/detail/R-HSA-2871796) | curated |
| [MAPK6/MAPK4 signaling](https://reactome.org/content/detail/R-HSA-5687128) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription repressor activity, RNA polymerase II-specific, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription factor activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of transcription by RNA polymerase II, transforming growth factor beta receptor signaling pathway, release from viral latency, transforming growth factor beta1 production, response to endoplasmic reticulum stress.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Center, National Cancer Institute | Pathogenic | no assertion criteria provided | research |  |

## Associated conditions {#conditions}

[breast neoplasm](https://sugi.bio/atlas/disease/breast-neoplasm/).

**Reported phenotype names (ClinVar):** Breast neoplasm, Breast Neoplasms, Neoplasm of breast, Breast tumor, Neoplasm of the breast.

## Similar variants {#similar}

Related JUN variant pages (same residue, condition, or type): [JUN p.Pro220Ala](/variant/jun-p-pro220ala).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1706623). 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.*