# NM_000546.6(TP53):c.329G>A (p.Arg110His)

https://sugi.bio/variant/tp53-p-arg110his

## Summary

**TP53 p.Arg110His (c.329G>A)** is classified **Likely benign** in TP53 (ClinVar, Expert panel, 15 submitters; last evaluated 2025-01-16). AlphaMissense: likely benign (0.0631); Very rare (popmax 0.00891%, eas); Associated with Li-Fraumeni syndrome.

**At a glance:** Likely benign · review: Expert panel · rsID rs11540654 · 15 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00891%, eas)

## For patients & families {#patients}

This is a change in the TP53 gene that is classified as likely benign — not considered disease-causing, submitted by 15 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.Arg110His |
| Coding change (HGVS c.) | c.329G>A |
| MANE Select transcript | [NM_000546](https://www.ncbi.nlm.nih.gov/nuccore/NM_000546) |
| dbSNP | [rs11540654](https://www.ncbi.nlm.nih.gov/snp/rs11540654/) |
| Variant type | single nucleotide variant |
| Location | chr17:7676040-7676040 (GRCh38) |
| ClinVar | [VCV127808](https://www.ncbi.nlm.nih.gov/clinvar/variation/127808/) |

**All HGVS expressions:** `LRG_321:g.16511G>A`, `LRG_321t1:c.329G>A`, `NC_000017.10:g.7579358C>T`, `NC_000017.11:g.7676040C>T`, `NG_017013.2:g.16511G>A`, `NM_000546.6:c.329G>A`, `NM_001126112.3:c.329G>A`, `NM_001126113.3:c.329G>A`, `NM_001126114.3:c.329G>A`, `NM_001126118.2:c.212G>A`, `NM_001276695.3:c.212G>A`, `NM_001276696.3:c.212G>A`, `NM_001276760.3:c.212G>A`, `NM_001276761.3:c.212G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0631)
- REVEL 0.592 (indeterminate)
- SaProt LLR -9.625 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP -4.064, GERP -4.42 — fast-evolving / accelerated position
- CADD: **PHRED 17.14**. 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 **0.00891%** (eas) · FAF95 0.00588% · FAF99 0.00541% · 4/44,872 in the highest group · 101/1,612,380 alleles overall — very rare (popmax 0.00891%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00891% | 11,218 |
| Admixed American | 0.00833% | 12,003 |
| Remaining individuals (not grpmax-eligible) | 0.00802% | 12,470 |
| European (non-Finnish) | 0.00712% | 14,048 |
| African / African-American | 0.00267% | 37,491 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,034 |

*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 **110** lies in a DNA-binding region; a β-strand; the 'interaction with ccar2' 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 a familial cancer not matching lfs; germline mutation and in sporadic cancers; somatic mutation; does not induce snai1 degradation); the 'interaction with wwox' 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.Arg110His 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}

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

**Submitter consensus:** conflicting (7 Uncertain significance, 5 Likely benign, 1 likely benign, 1 not provided, 1 Likely Benign).

**Submission history:** 15 submissions (2013–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — TP53 VCEP (Li-Fraumeni syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS2_Moderate`, `BP4`, `BS3_Supporting`.
*Considered but not met:* `PM2`, `PS1`, `PS2`, `PS3`, `PS4`, `PM1`, `PP1`, `PP3`, `BS1`, `BS4`, `BP5`, `PM5`, `BP2`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000546.6: c.329G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 110 (p.Arg110His). 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 contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007119 (84/1,180,010 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0728; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -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). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3_Supporting, BP4. (Bayesian Points: -4; VCEP specifications version 2.1; 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/00b45dfa-19f3-45de-975a-7b43bbc2be44).*
*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 |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-04-30 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | likely benign | criteria provided, single submitter | clinical testing | 2025-04-24 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2022-02-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-06 |
| ITMI | not provided | no classification provided | reference population | 2013-09-19 |
| True Health Diagnostics | Uncertain significance | no assertion criteria provided | clinical testing | 2018-08-09 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-12-10 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-04-26 |
| Myriad Genetics, Inc. | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-12 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-25 |
| ClinGen TP53 Variant Curation Expert Panel, ClinGen | Likely Benign | reviewed by expert panel | curation | 2025-01-16 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2016-01-27 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-14 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2021-07-20 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Li-Fraumeni syndrome, Hereditary cancer-predisposing syndrome, not specified, Li-Fraumeni syndrome 1, not provided, Malignant tumor of breast, TP53-related disorder, TP53-related condition, AllHighlyPenetrant, Tumor predisposition.

## Same-residue context {#hotspot}

Residue **110** carries **5 other pathogenic ClinVar variants** — a recurrently-mutated position: [TP53 p.Arg110fs](/variant/tp53-p-arg110fs), [TP53 p.Arg110_Phe113del](/variant/tp53-p-arg110-phe113del), [TP53 p.Arg110Pro](/variant/tp53-p-arg110pro), [TP53 p.Arg110Leu](/variant/tp53-p-arg110leu), [TP53 p.Arg110Gly](/variant/tp53-p-arg110gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TP53 variant pages (same residue, condition, or type): [TP53 p.Arg110Gly](/variant/tp53-p-arg110gly), [TP53 p.Arg110Leu](/variant/tp53-p-arg110leu), [TP53 p.Arg110Pro](/variant/tp53-p-arg110pro), [TP53 p.Arg110Cys](/variant/tp53-p-arg110cys), [TP53 p.Arg110Ser](/variant/tp53-p-arg110ser), [TP53 p.Arg110=](/variant/tp53-p-arg110), [TP53 p.Arg110_Phe113del](/variant/tp53-p-arg110-phe113del), [TP53 p.Arg110fs](/variant/tp53-p-arg110fs).

### 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 127808). 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.*