# NM_000546.6(TP53):c.215C>A (p.Pro72His)

https://sugi.bio/variant/tp53-p-pro72his

## Summary

**TP53 p.Pro72His (c.215C>A)** is classified **Benign** in TP53 (ClinVar, Expert panel, 8 submitters; last evaluated 2025-01-16). AlphaMissense: likely benign (0.0961); Very rare (popmax 0.0022%, sas); Associated with Li-Fraumeni syndrome.

**At a glance:** Benign · review: Expert panel · rsID rs1042522 · 8 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the TP53 gene that is classified as benign — not considered disease-causing, submitted by 8 submitters, 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.Pro72His |
| Coding change (HGVS c.) | c.215C>A |
| MANE Select transcript | [NM_000546](https://www.ncbi.nlm.nih.gov/nuccore/NM_000546) |
| dbSNP | [rs1042522](https://www.ncbi.nlm.nih.gov/snp/rs1042522/) |
| Variant type | single nucleotide variant |
| Location | chr17:7676154-7676154 (GRCh38) |
| ClinVar | [VCV185120](https://www.ncbi.nlm.nih.gov/clinvar/variation/185120/) |

**All HGVS expressions:** `LRG_321:g.16397C>A`, `LRG_321t1:c.215C>A`, `LRG_321t2:c.215C>A`, `NC_000017.10:g.7579472G>T`, `NC_000017.11:g.7676154G>T`, `NG_017013.2:g.16397C>A`, `NM_000546.6:c.215C>A`, `NM_001126112.3:c.215C>A`, `NM_001126113.3:c.215C>A`, `NM_001126114.3:c.215C>A`, `NM_001126118.2:c.98C>A`, `NM_001276695.3:c.98C>A`, `NM_001276696.3:c.98C>A`, `NM_001276760.3:c.98C>A`, `NM_001276761.3:c.98C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0961)
- REVEL 0.352 (indeterminate)
- SaProt LLR -10.61 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 1.509, GERP 1.09, phastCons 0.015 — weakly conserved position
- CADD: **PHRED 16.14**. 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 (gnomAD v4.1): grpmax **0.0022%** (sas) · FAF95 0.0005% · FAF99 0.000366% · 2/91,052 in the highest group · 14/1,461,570 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0022% | 45,526 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,476 |
| European (non-Finnish) | 0.000932% | 107,271 |

*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 **72** lies in a UniProt-annotated variant site (in sporadic cancers; somatic mutation; requires 2 nucleotide substitutions); 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); the 'interaction with ccar2' region; the 'interaction with hrmt1l2' region; the 'disordered' region; the 'interaction with wwox' 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.Pro72His falls in the interaction with ccar2 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}

**Benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-01-16.

**Submitter consensus:** conflicting (4 Uncertain significance, 2 Likely benign, 1 Benign, 1 Uncertain Significance).

**Submission history:** 8 submissions (2021–2026); classifications have differed over time.

**ClinGen expert panel:** Benign — TP53 VCEP (Li-Fraumeni syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `BS2_Moderate`, `BS3`, `BP4_Moderate`.
*Considered but not met:* `PM6`, `PS1`, `PS2`, `PS3`, `PS4`, `PM1`, `PP1`, `PP3`, `PP4`, `BS1`, `BS4`, `PM5`, `BP2`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000546.6: c.215C>A variant in TP53 is a missense variant predicted to cause substitution of proline by histidine at amino acid 72 (p.Pro72His). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: LabCorp Genetics). This variant has an allele frequency of 0.00002197 (2/91052 alleles) in the South Asian population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644).  Computational predictor scores (BayesDel = -0.1017; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -7; VCEP specifications version 2.0; 1/16/2025)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50013 · approved 2025-01-16 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/5b6326a9-cfce-4111-96c4-46eaacd8c2df).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-03-26 |
| ClinGen TP53 Variant Curation Expert Panel, ClinGen | Benign | reviewed by expert panel | curation | 2025-01-16 |
| Sema4, Sema4 | Uncertain significance | criteria provided, single submitter | curation | 2022-03-10 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-07-01 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-08 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-04 |
| All of Us Research Program, National Institutes of Health | Uncertain Significance | criteria provided, single submitter | clinical testing | 2023-03-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-05 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Li-Fraumeni syndrome, Hereditary cancer-predisposing syndrome, TP53-related disorder, not provided, TP53-related condition, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, none provided.

## Same-residue context {#hotspot}

Residue **72** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TP53 p.Pro72fs](/variant/tp53-p-pro72fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Pharmacogenomics (PharmGKB) {#pgx}

Clinical drug-response annotations:

| Drug(s) | Evidence level | Category | Phenotype |
| --- | --- | --- | --- |
| antineoplastic agents | 3 | Toxicity | Drug Toxicity |
| Platinum compounds | 3 | Efficacy | Overall survival |
*PharmGKB levels 1A/1B (highest) → 4. Discuss any medication decision with your prescriber — reference information, not advice.*

## Similar variants {#similar}

Related TP53 variant pages (same residue, condition, or type): [TP53 p.Pro72Ala](/variant/tp53-p-pro72ala), [TP53 p.Pro72Arg](/variant/tp53-p-pro72arg), [TP53 p.Pro72Leu](/variant/tp53-p-pro72leu), [TP53 p.Pro72Thr](/variant/tp53-p-pro72thr), [TP53 p.Pro72Cys](/variant/tp53-p-pro72cys), [TP53 p.Pro72Ser](/variant/tp53-p-pro72ser), [TP53 p.Pro72fs](/variant/tp53-p-pro72fs), [TP53 p.Pro72_Val73delinsArgMet](/variant/tp53-p-pro72-val73delinsargmet).

### 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 185120). 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.*