# NM_000546.6(TP53):c.1007_1008dup (p.Arg337fs)

https://sugi.bio/variant/tp53-p-arg337fs

## Summary

**TP53 p.Arg337fs (c.1007_1008dup)** is classified **Pathogenic** in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-16). No gnomAD frequency available for this variant; Associated with Li-Fraumeni syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2543474198 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the TP53 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Li-Fraumeni 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (United Kingdom) |
| Clinical trials | 21 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TP53 is a diagnostic-grade gene on 19 Genomics England panels |

**Commonly reported features of Li-Fraumeni syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Neoplasm — Very frequent (99-80%)
- Breast carcinoma — Frequent (79-30%)
- Leukemia — Occasional (29-5%)
- Lymphoma — Occasional (29-5%)
- Osteosarcoma — Occasional (29-5%)
- Rhabdomyosarcoma — Occasional (29-5%)
- Ependymoma — Occasional (29-5%)
- Adrenocortical carcinoma — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006902/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TP53](https://sugi.bio/atlas/gene/TP53/) |
| Protein change (HGVS p.) | p.Arg337fs |
| Coding change (HGVS c.) | c.1007_1008dup |
| MANE Select transcript | [NM_000546](https://www.ncbi.nlm.nih.gov/nuccore/NM_000546) |
| dbSNP | [rs2543474198](https://www.ncbi.nlm.nih.gov/snp/rs2543474198/) |
| Variant type | Duplication |
| Location | chr17:7670700-7670701 (GRCh38) |
| ClinVar | [VCV2753213](https://www.ncbi.nlm.nih.gov/clinvar/variation/2753213/) |

**All HGVS expressions:** `LRG_321:g.21849_21850dup`, `LRG_321t1:c.1006_1007dup`, `LRG_321t2:c.1006_1007dup`, `LRG_321t3:c.*113_*114dup`, `LRG_321t4:c.*25_*26dup`, `LRG_321t5:c.610_611dup`, `LRG_321t6:c.*113_*114dup`, `LRG_321t7:c.*25_*26dup`, `LRG_321t8:c.889_890dup`, `NC_000017.10:g.7574020_7574021dup`, `NC_000017.11:g.7670702_7670703dup`, `NG_017013.2:g.21849_21850dup`, `NM_000546.6:c.1007_1008dup`, `NM_001126112.3:c.1007_1008dup`, `NM_001126113.3:c.*26_*27dup`, `NM_001126114.3:c.*114_*115dup`, `NM_001126115.2:c.611_612dup`, `NM_001126116.2:c.*114_*115dup`, `NM_001126117.2:c.*26_*27dup`, `NM_001126118.2:c.890_891dup`, `NM_001276695.3:c.*26_*27dup`, `NM_001276696.3:c.*114_*115dup`, `NM_001276697.3:c.530_531dup`, `NM_001276698.3:c.*114_*115dup`, `NM_001276699.3:c.*26_*27dup`, `NM_001276760.3:c.890_891dup`, `NM_001276761.3:c.890_891dup`, `NM_001407262.1:c.1007_1008dup`, `NM_001407263.1:c.890_891dup`, `NM_001407264.1:c.1007_1008dup`, `NM_001407265.1:c.890_891dup`, `NM_001407266.1:c.1007_1008dup`, `NM_001407267.1:c.890_891dup`, `NM_001407268.1:c.*114_*115dup`, `NM_001407269.1:c.*114_*115dup`, `NM_001407270.1:c.*114_*115dup`, `NM_001407271.1:c.*114_*115dup`, `NR_176326.1:n.1036_1037dup`

## 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 6.547, GERP 0.923, 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 (constraint LOEUF 0.449, pLI 0.99798), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 11**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- 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}

**TP53** population constraint: LOEUF 0.449, pLI 0.99798, missense-Z 1.1539; 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):

- **Li-Fraumeni syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **337** lies in a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation; impaired ability to tetramerize and undergo liquid-liquid phase separation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation; impaired ability to tetramerize and undergo liquid-liquid phase separation); the 'interaction with carm1' region; an α-helix; the 'interaction with hipk2' region; the 'oligomerization' region; a modified residue (symmetric dimethylarginine; by prmt5); the 'interaction with hipk1' region.

AlphaFold model confidence (whole protein): pLDDT 75.83, 54% of residues very-high.

**321 experimental structure(s)** (PDB): [1A1U](https://www.rcsb.org/structure/1A1U), [1AIE](https://www.rcsb.org/structure/1AIE), [1C26](https://www.rcsb.org/structure/1C26), [1DT7](https://www.rcsb.org/structure/1DT7), [1GZH](https://www.rcsb.org/structure/1GZH), [1H26](https://www.rcsb.org/structure/1H26) — incl. mutant structure 1A1U.

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

*Describes the biological roles of TP53 (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:** TP53's established molecular role includes transcription cis-regulatory region binding. p.Arg337fs falls in the interaction with carm1 region. In Reactome, TP53 is annotated in disease pathway(s) including **Loss of function of TP53 in cancer due to loss of tetramerization ability**, **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** TP53 loss or alteration is curated in [Loss of function of TP53 in cancer due to loss of tetramerization ability](https://reactome.org/content/detail/R-HSA-9723905), [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370).

### Pathways affected {#pathways}

TP53 participates in **47 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Loss of function of TP53 in cancer due to loss of tetramerization ability](https://reactome.org/content/detail/R-HSA-9723905) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| [Activation of NOXA and translocation to mitochondria](https://reactome.org/content/detail/R-HSA-111448) | curated |
| [Activation of PUMA and translocation to mitochondria](https://reactome.org/content/detail/R-HSA-139915) | curated |
| [Autodegradation of the E3 ubiquitin ligase COP1](https://reactome.org/content/detail/R-HSA-349425) | curated |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [Formation of Senescence-Associated Heterochromatin Foci (SAHF)](https://reactome.org/content/detail/R-HSA-2559584) | curated |
| [G2/M Checkpoints](https://reactome.org/content/detail/R-HSA-69481) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [Negative transcriptional regulation of urea cycle enzymes](https://reactome.org/content/detail/R-HSA-9988426) | curated |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | curated |
| [Ovarian tumor domain proteases](https://reactome.org/content/detail/R-HSA-5689896) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [PI5P Regulates TP53 Acetylation](https://reactome.org/content/detail/R-HSA-6811555) | curated |
| [PKR-mediated signaling](https://reactome.org/content/detail/R-HSA-9833482) | curated |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | curated |
| [Pyroptosis](https://reactome.org/content/detail/R-HSA-5620971) | curated |
| [RUNX3 regulates CDKN1A transcription](https://reactome.org/content/detail/R-HSA-8941855) | curated |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |
| [Regulation of NF-kappa B signaling](https://reactome.org/content/detail/R-HSA-9758274) | curated |
| [Regulation of TP53 Activity through Acetylation](https://reactome.org/content/detail/R-HSA-6804758) | curated |
| [Regulation of TP53 Activity through Association with Co-factors](https://reactome.org/content/detail/R-HSA-6804759) | curated |
| [Regulation of TP53 Activity through Methylation](https://reactome.org/content/detail/R-HSA-6804760) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [Regulation of TP53 Expression](https://reactome.org/content/detail/R-HSA-6804754) | curated |
| [SUMOylation of transcription factors](https://reactome.org/content/detail/R-HSA-3232118) | curated |
| [Stabilization of p53](https://reactome.org/content/detail/R-HSA-69541) | curated |
| [TP53 Regulates Metabolic Genes](https://reactome.org/content/detail/R-HSA-5628897) | curated |
| [TP53 Regulates Transcription of Caspase Activators and Caspases](https://reactome.org/content/detail/R-HSA-6803207) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [TP53 Regulates Transcription of Death Receptors and Ligands](https://reactome.org/content/detail/R-HSA-6803211) | curated |
| [TP53 Regulates Transcription of Genes Involved in Cytochrome C Release](https://reactome.org/content/detail/R-HSA-6803204) | curated |
| [TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest](https://reactome.org/content/detail/R-HSA-6804116) | curated |
| [TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest](https://reactome.org/content/detail/R-HSA-6804114) | curated |
| [TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain](https://reactome.org/content/detail/R-HSA-6804115) | curated |
| [TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain](https://reactome.org/content/detail/R-HSA-6803205) | curated |
| [The role of GTSE1 in G2/M progression after G2 checkpoint](https://reactome.org/content/detail/R-HSA-8852276) | curated |
| [Transcriptional  activation of  cell cycle inhibitor p21 ](https://reactome.org/content/detail/R-HSA-69895) | curated |
| [Transcriptional Regulation by VENTX](https://reactome.org/content/detail/R-HSA-8853884) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [Association of TriC/CCT with target proteins during biosynthesis](https://reactome.org/content/detail/R-HSA-390471) | electronic |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | electronic |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | electronic |
| [Urea cycle](https://reactome.org/content/detail/R-HSA-70635) | other |
| [Zygotic genome activation (ZGA)](https://reactome.org/content/detail/R-HSA-9819196) | 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, cis-regulatory region sequence-specific DNA binding, core promoter sequence-specific DNA binding, TFIID-class transcription factor complex binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, hematopoietic progenitor cell differentiation, nucleotide-excision repair, regulation of DNA-templated transcription, regulation of transcription by RNA polymerase II, autophagy.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-16.

**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 | 2023-08-16 |

## Associated conditions {#conditions}

[Li-Fraumeni syndrome](https://sugi.bio/atlas/disease/li-fraumeni-syndrome/).

**Reported phenotype names (ClinVar):** Li-Fraumeni syndrome, Sarcoma family syndrome of Li and Fraumeni.

## Same-residue context {#hotspot}

Residue **337** carries **5 other pathogenic ClinVar variants** — a recurrently-mutated position: [TP53 p.Arg337Ser](/variant/tp53-p-arg337ser), [TP53 p.Arg337Cys](/variant/tp53-p-arg337cys), [TP53 p.Arg337Leu](/variant/tp53-p-arg337leu), [TP53 p.Arg337Pro](/variant/tp53-p-arg337pro), [TP53 p.Arg337Gly](/variant/tp53-p-arg337gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TP53 variant pages (same residue, condition, or type): [TP53 p.Arg337Cys](/variant/tp53-p-arg337cys), [TP53 p.Arg337Gly](/variant/tp53-p-arg337gly), [TP53 p.Arg337Leu](/variant/tp53-p-arg337leu), [TP53 p.Arg337Pro](/variant/tp53-p-arg337pro), [TP53 p.Arg337Ser](/variant/tp53-p-arg337ser), [TP53 p.Ter394LeuextTer?](/variant/tp53-p-ter394leuextter), [TP53 c.375+1dup](/variant/tp53-c-375-plus-1dup), [TP53 c.97-1_102dup](/variant/tp53-c-97-minus-1-102dup).

### 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 2026-07-14); 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 2753213). 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.*