# NM_003722.5(TP63):c.1042C>G (p.Pro348Ala)

https://sugi.bio/variant/tp63-p-pro348ala

## Summary

**TP63 p.Pro348Ala (c.1042C>G)** is classified **Uncertain significance** in TP63 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-15). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with TP63-Related Spectrum Disorders.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1577147850 · 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 currently of uncertain significance — a definitive interpretation has not yet been established, 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.Pro348Ala |
| Coding change (HGVS c.) | c.1042C>G |
| MANE Select transcript | [NM_003722](https://www.ncbi.nlm.nih.gov/nuccore/NM_003722) |
| dbSNP | [rs1577147850](https://www.ncbi.nlm.nih.gov/snp/rs1577147850/) |
| Variant type | single nucleotide variant |
| Location | chr3:189868629-189868629 (GRCh38) |
| ClinVar | [VCV659864](https://www.ncbi.nlm.nih.gov/clinvar/variation/659864/) |

**All HGVS expressions:** `LRG_428:g.276884C>G`, `LRG_428t1:c.1042C>G`, `NC_000003.11:g.189586418C>G`, `NC_000003.12:g.189868629C>G`, `NG_007550.3:g.276884C>G`, `NM_001114978.2:c.1042C>G`, `NM_001114979.2:c.1042C>G`, `NM_001114980.2:c.760C>G`, `NM_001114981.2:c.760C>G`, `NM_001114982.2:c.760C>G`, `NM_001329144.2:c.1042C>G`, `NM_001329145.2:c.760C>G`, `NM_001329146.2:c.505C>G`, `NM_001329148.2:c.1042C>G`, `NM_001329149.2:c.760C>G`, `NM_001329150.2:c.505C>G`, `NM_001329964.2:c.1036C>G`, `NM_003722.5:c.1042C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9996)
- REVEL 0.852 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.592 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.669, GERP 1.94, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in TP63 (of 4,040 modeled).
- CADD: **PHRED 25.8**. 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 0.35** across the covering region of the MANE Select transcript (189,866,793–189,868,655), spanning 1,862 bp — the region is depleted of missense variation. Chi-square p 2.1e-09. 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 **348** lies in an α-helix; a DNA-binding region; a UniProt-annotated variant site (in eec3).

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.Pro348Ala falls in a DNA-binding region.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-08-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-08-15 |

## 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 **348** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TP63 p.Pro348Ser](/variant/tp63-p-pro348ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TP63 variant pages (same residue, condition, or type): [TP63 p.Pro348Leu](/variant/tp63-p-pro348leu), [TP63 p.Pro348=](/variant/tp63-p-pro348), [TP63 p.Pro348Ser](/variant/tp63-p-pro348ser), [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).

### 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 659864). 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.*