# NM_003722.5(TP63):c.1693_1694del (p.Phe565fs)

https://sugi.bio/variant/tp63-p-phe565fs

## Summary

**TP63 p.Phe565fs (c.1693_1694del)** is classified **Pathogenic** in TP63 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2008-08-01). No gnomAD frequency available for this variant; Associated with limb-mammary syndrome.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs2108864814 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the TP63 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to limb-mammary 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010051/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.Phe565fs |
| Coding change (HGVS c.) | c.1693_1694del |
| MANE Select transcript | [NM_003722](https://www.ncbi.nlm.nih.gov/nuccore/NM_003722) |
| dbSNP | [rs2108864814](https://www.ncbi.nlm.nih.gov/snp/rs2108864814/) |
| Variant type | Deletion |
| Location | chr3:189890828-189890829 (GRCh38) |
| ClinVar | [VCV6538](https://www.ncbi.nlm.nih.gov/clinvar/variation/6538/) |

**All HGVS expressions:** `LRG_428:g.299084_299085del`, `LRG_428t1:c.1693_1694del`, `NC_000003.11:g.189608618_189608619del`, `NC_000003.12:g.189890829_189890830del`, `NG_007550.3:g.299084_299085del`, `NM_001114978.2:c.1652+1345_1652+1346del`, `NM_001114980.2:c.1411_1412del`, `NM_001114981.2:c.1370+1345_1370+1346del`, `NM_001329144.2:c.1508-3377_1508-3376del`, `NM_001329145.2:c.1226-3377_1226-3376del`, `NM_001329146.2:c.1156_1157del`, `NM_001329148.2:c.1681_1682del`, `NM_001329149.2:c.1214-3377_1214-3376del`, `NM_001329150.2:c.959-3377_959-3376del`, `NM_001329964.2:c.1687_1688del`, `NM_003722.5:c.1693_1694del`

## 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 11.229, GERP 2.85, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.296, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 13 of 14**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**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 **565** lies in the sam domain; an α-helix.

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.Phe565fs 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}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2008-08-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2008-08-01 |

## Associated conditions {#conditions}

[limb-mammary syndrome](https://sugi.bio/atlas/disease/limb-mammary-syndrome/).

**Reported phenotype names (ClinVar):** Limb-mammary syndrome, Mammary hypoplasia, ectrodactyly, and other hand/foot anomalies.

## Same-residue context {#hotspot}

Residue **565** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [TP63 p.Phe565Leu](/variant/tp63-p-phe565leu), [TP63 p.Phe565Val](/variant/tp63-p-phe565val). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TP63 variant pages (same residue, condition, or type): [TP63 c.192-9_192-8del](/variant/tp63-c-192-minus-9-192-minus-8del), [TP63 p.Phe565Leu](/variant/tp63-p-phe565leu), [TP63 p.Phe565Val](/variant/tp63-p-phe565val), [TP63 p.Ser621fs](/variant/tp63-p-ser621fs), [TP63 p.Arg243Trp](/variant/tp63-p-arg243trp), [TP63 p.Arg343Gln](/variant/tp63-p-arg343gln), [TP63 p.Arg655Ter](/variant/tp63-p-arg655ter), [TP63 c.1507+6_1507+7del](/variant/tp63-c-1507-plus-6-1507-plus-7del).

### 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 6538). 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.*