# NM_000546.6(TP53):c.800G>C (p.Arg267Pro)

https://sugi.bio/variant/tp53-p-arg267pro

## Summary

**TP53 p.Arg267Pro (c.800G>C)** is classified **Pathogenic** in TP53 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-25). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs587780075 · 3 submitters · 3 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TP53 gene that is considered disease-causing, submitted by 3 submitters, 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 | [TP53](https://sugi.bio/atlas/gene/TP53/) |
| Protein change (HGVS p.) | p.Arg267Pro |
| Coding change (HGVS c.) | c.800G>C |
| MANE Select transcript | [NM_000546](https://www.ncbi.nlm.nih.gov/nuccore/NM_000546) |
| dbSNP | [rs587780075](https://www.ncbi.nlm.nih.gov/snp/rs587780075/) |
| Variant type | single nucleotide variant |
| Location | chr17:7673820-7673820 (GRCh38) |
| ClinVar | [VCV428867](https://www.ncbi.nlm.nih.gov/clinvar/variation/428867/) |

**All HGVS expressions:** `LRG_321:g.18731G>C`, `LRG_321t1:c.800G>C`, `NC_000017.10:g.7577138C>G`, `NC_000017.11:g.7673820C>G`, `NG_017013.2:g.18731G>C`, `NM_000546.6:c.800G>C`, `NM_001126112.3:c.800G>C`, `NM_001126113.3:c.800G>C`, `NM_001126114.3:c.800G>C`, `NM_001126115.2:c.404G>C`, `NM_001126116.2:c.404G>C`, `NM_001126117.2:c.404G>C`, `NM_001126118.2:c.683G>C`, `NM_001276695.3:c.683G>C`, `NM_001276696.3:c.683G>C`, `NM_001276697.3:c.323G>C`, `NM_001276698.3:c.323G>C`, `NM_001276699.3:c.323G>C`, `NM_001276760.3:c.683G>C`, `NM_001276761.3:c.683G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9992) — concordant with the pathogenic call
- REVEL 0.927 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -17.751 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 4.944, GERP 1.53, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in TP53 (of 2,314 modeled).
- CADD: **PHRED 27.7**. 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 0.89** across the covering region of the MANE Select transcript (7,669,612–7,676,594), spanning 6,982 bp. Chi-square p 0.0085. 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}

**TP53** population constraint: LOEUF 0.449, pLI 0.99798, missense-Z 1.1539; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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 **267** lies in a DNA-binding region; the 'interaction with axin1' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation); the 'interaction with e4f1' region; a β-strand; the 'interaction with ccar2' region; the 'interaction with hipk1' region; the 'required for interaction with znf385a' 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.Arg267Pro falls in a DNA-binding 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-02-25.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-25 |
| Ayesha Lab, University of the Punjab | Likely pathogenic | no assertion criteria provided | clinical testing |  |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [acute myeloid leukemia](https://sugi.bio/atlas/disease/acute-myeloid-leukemia/), [Li-Fraumeni syndrome](https://sugi.bio/atlas/disease/li-fraumeni-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Li-Fraumeni syndrome, Acute myeloid leukemia, Hereditary neoplastic syndrome, Tumor predisposition, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, CEBPA-Associated Familial Acute Myeloid Leukemia (AML), Leukemia, acute myeloid, somatic, Acute myeloid leukemia, adult.

## Same-residue context {#hotspot}

Residue **267** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [TP53 p.Arg267Trp](/variant/tp53-p-arg267trp), [TP53 p.Arg267Gly](/variant/tp53-p-arg267gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TP53 variant pages (same residue, condition, or type): [TP53 p.Arg267Gln](/variant/tp53-p-arg267gln), [TP53 p.Arg267Gly](/variant/tp53-p-arg267gly), [TP53 p.Arg267Trp](/variant/tp53-p-arg267trp), [TP53 p.Arg267Leu](/variant/tp53-p-arg267leu), [TP53 p.Arg267=](/variant/tp53-p-arg267), [TP53 c.375+5G>A](/variant/tp53-c-375-plus-5g-a), [TP53 c.919+1G>A](/variant/tp53-c-919-plus-1g-a), [TP53 c.97-1G>A](/variant/tp53-c-97-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 428867). 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.*