# NM_003722.5(TP63):c.1626G>A (p.Pro542=)

https://sugi.bio/variant/tp63-p-pro542

## Summary

**TP63 p.Pro542= (c.1626G>A)** is classified **Likely benign** in TP63 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-30). Ultra-rare (popmax 0.03%, amr); Associated with ADULT syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs370637253 · 3 submitters · 7 linked conditions · ultra-rare (popmax 0.03%, amr)

## For patients & families {#patients}

This is a change in the TP63 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to ADULT 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 | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000384/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TP63](https://sugi.bio/atlas/gene/TP63/) |
| Protein change (HGVS p.) | p.Pro542= |
| Coding change (HGVS c.) | c.1626G>A |
| MANE Select transcript | [NM_003722](https://www.ncbi.nlm.nih.gov/nuccore/NM_003722) |
| dbSNP | [rs370637253](https://www.ncbi.nlm.nih.gov/snp/rs370637253/) |
| Variant type | single nucleotide variant |
| Location | chr3:189889458-189889458 (GRCh38) |
| ClinVar | [VCV1110153](https://www.ncbi.nlm.nih.gov/clinvar/variation/1110153/) |

**All HGVS expressions:** `LRG_428:g.297713G>A`, `LRG_428t1:c.1626G>A`, `NC_000003.11:g.189607247G>A`, `NC_000003.12:g.189889458G>A`, `NG_007550.3:g.297713G>A`, `NM_001114978.2:c.1626G>A`, `NM_001114980.2:c.1344G>A`, `NM_001114981.2:c.1344G>A`, `NM_001329144.2:c.1507+2907G>A`, `NM_001329145.2:c.1225+2907G>A`, `NM_001329146.2:c.1089G>A`, `NM_001329148.2:c.1614G>A`, `NM_001329149.2:c.1213+2907G>A`, `NM_001329150.2:c.958+2907G>A`, `NM_001329964.2:c.1620G>A`, `NM_003722.4:c.1626G>A`, `NM_003722.5:c.1626G>A`

## 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 1.54, GERP -2.03, phastCons 1 — weakly conserved position
- CADD: **PHRED 11.93**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.22 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.03%** (amr) · FAF95 0.0194% · FAF99 0.016% · 18/59,974 in the highest group · 47/1,613,560 alleles overall — ultra-rare (popmax 0.03%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.03% | 3,332 |
| African / African-American | 0.00669% | 14,953 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,237 |
| European (non-Finnish) | 0.00178% | 56,185 |
| South Asian | 0.0011% | 91,056 |

*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}

**TP63** population constraint: LOEUF 0.296, pLI 1, missense-Z 3.5197; ClinGen dosage — haploinsufficiency 1/3, 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):

- **ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3** — Definitive (AD)

## Protein context {#protein}

Residue **542** lies in the sam domain.

AlphaFold model confidence (whole protein): pLDDT 63.70, 35% of residues very-high.

**26 experimental structure(s)** (PDB): [1RG6](https://www.rcsb.org/structure/1RG6), [2NB1](https://www.rcsb.org/structure/2NB1), [2RMN](https://www.rcsb.org/structure/2RMN), [2Y9T](https://www.rcsb.org/structure/2Y9T), [2Y9U](https://www.rcsb.org/structure/2Y9U), [3QYM](https://www.rcsb.org/structure/3QYM) — incl. mutant structure 2Y9T.

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

*Describes the biological roles of TP63 (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:** TP63's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. p.Pro542= falls in the sam domain.


### Pathways affected {#pathways}

TP63 participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of PUMA and translocation to mitochondria](https://reactome.org/content/detail/R-HSA-139915) | curated |
| [Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin](https://reactome.org/content/detail/R-HSA-9725554) | curated |
| [Pyroptosis](https://reactome.org/content/detail/R-HSA-5620971) | curated |
| [Regulation of TP53 Activity through Association with Co-factors](https://reactome.org/content/detail/R-HSA-6804759) | 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 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 several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain](https://reactome.org/content/detail/R-HSA-6803205) | curated |
| [Developmental Lineage of Mammary Gland Luminal Epithelial Cells](https://reactome.org/content/detail/R-HSA-9927418) | other |
| [Developmental Lineage of Mammary Gland Myoepithelial Cells](https://reactome.org/content/detail/R-HSA-9927432) | other |
| [Developmental Lineage of Mammary Stem Cells](https://reactome.org/content/detail/R-HSA-9938206) | other |

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

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, p53 binding, chromatin binding, DNA-binding transcription factor activity, identical protein binding, WW domain binding.

**Biological process:** DNA damage response, positive regulation of osteoblast differentiation, positive regulation of Notch signaling pathway, negative regulation of DNA-templated transcription, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-30.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-01-18 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-04-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-30 |

## Associated conditions {#conditions}

[ADULT syndrome](https://sugi.bio/atlas/disease/adult-syndrome/), [ankyloblepharon-ectodermal defects-cleft lip/palate syndrome](https://sugi.bio/atlas/disease/ankyloblepharon-ectodermal-defects-cleft-lip-palate-syndrome/), [Rapp-Hodgkin syndrome](https://sugi.bio/atlas/disease/rapp-hodgkin-syndrome/), [limb-mammary syndrome](https://sugi.bio/atlas/disease/limb-mammary-syndrome/), [ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3](https://sugi.bio/atlas/disease/ectrodactyly-ectodermal-dysplasia-and-cleft-lip-palate-syndrome-3/), [split hand-foot malformation 4](https://sugi.bio/atlas/disease/split-hand-foot-malformation-4/), [orofacial cleft 8](https://sugi.bio/atlas/disease/orofacial-cleft-8/).

**Reported phenotype names (ClinVar):** ADULT syndrome, TP63-Related Spectrum Disorders, Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, Limb-mammary syndrome, Orofacial cleft 8, Rapp-Hodgkin syndrome, Split hand-foot malformation 4, TP63-related disorder, ACRO-DERMATO-UNGUAL-LACRIMAL-TOOTH SYNDROME.

## Similar variants {#similar}

Related TP63 variant pages (same residue, condition, or type): [TP63 p.Ala354Glu](/variant/tp63-p-ala354glu), [TP63 p.Arg243Gln](/variant/tp63-p-arg243gln), [TP63 p.Arg243Trp](/variant/tp63-p-arg243trp), [TP63 p.Arg266Gln](/variant/tp63-p-arg266gln), [TP63 p.Arg318Cys](/variant/tp63-p-arg318cys), [TP63 p.Arg318His](/variant/tp63-p-arg318his), [TP63 p.Arg319Cys](/variant/tp63-p-arg319cys), [TP63 p.Arg319His](/variant/tp63-p-arg319his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1110153). 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.*