# NM_003722.5(TP63):c.1693T>G (p.Phe565Val)

https://sugi.bio/variant/tp63-p-phe565val

## Summary

**TP63 p.Phe565Val (c.1693T>G)** is classified **Pathogenic** in TP63 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-10-30). AlphaMissense: likely pathogenic (0.9694); Absent from gnomAD v4.1; Associated with TP63-Related Spectrum Disorders.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1577206350 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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 TP63-Related Spectrum Disorders.

*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:** [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.Phe565Val |
| Coding change (HGVS c.) | c.1693T>G |
| MANE Select transcript | [NM_003722](https://www.ncbi.nlm.nih.gov/nuccore/NM_003722) |
| dbSNP | [rs1577206350](https://www.ncbi.nlm.nih.gov/snp/rs1577206350/) |
| Variant type | single nucleotide variant |
| Location | chr3:189890829-189890829 (GRCh38) |
| ClinVar | [VCV650415](https://www.ncbi.nlm.nih.gov/clinvar/variation/650415/) |

**All HGVS expressions:** `LRG_428:g.299084T>G`, `LRG_428t1:c.1693T>G`, `NC_000003.11:g.189608618T>G`, `NC_000003.12:g.189890829T>G`, `NG_007550.3:g.299084T>G`, `NM_001114978.2:c.1652+1345T>G`, `NM_001114980.2:c.1411T>G`, `NM_001114981.2:c.1370+1345T>G`, `NM_001329144.2:c.1508-3377T>G`, `NM_001329145.2:c.1226-3377T>G`, `NM_001329146.2:c.1156T>G`, `NM_001329148.2:c.1681T>G`, `NM_001329149.2:c.1214-3377T>G`, `NM_001329150.2:c.959-3377T>G`, `NM_001329964.2:c.1687T>G`, `NM_003722.5:c.1693T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9694) — concordant with the pathogenic call
- REVEL 0.884 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.232 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.899, GERP 2.85, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.2**. 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 0.80** across the covering region of the MANE Select transcript (189,868,656–189,894,499), spanning 25,843 bp. Chi-square p 4.9e-05. 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}

**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.Phe565Val 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2018-10-30.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2018-10-30 |

## Associated conditions {#conditions}

[TP63-Related Spectrum Disorders](https://sugi.bio/atlas/disease/tp63-related-spectrum-disorders/).

**Reported phenotype names (ClinVar):** TP63-Related Spectrum Disorders.

## 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.Phe565fs](/variant/tp63-p-phe565fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TP63 variant pages (same residue, condition, or type): [TP63 p.Phe565Leu](/variant/tp63-p-phe565leu), [TP63 p.Arg318His](/variant/tp63-p-arg318his), [TP63 p.Cys561Tyr](/variant/tp63-p-cys561tyr), [TP63 p.Gly173Arg](/variant/tp63-p-gly173arg), [TP63 p.Gly173Asp](/variant/tp63-p-gly173asp), [TP63 p.Gly336Asp](/variant/tp63-p-gly336asp), [TP63 p.Gly557Val](/variant/tp63-p-gly557val), [TP63 p.His247Arg](/variant/tp63-p-his247arg).

### 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 650415). 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.*