# NM_003722.5(TP63):c.122C>T (p.Ser41Phe)

https://sugi.bio/variant/tp63-p-ser41phe

## Summary

**TP63 p.Ser41Phe (c.122C>T)** is classified **Uncertain significance** in TP63 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-21). AlphaMissense: likely benign (0.2429); Very rare (popmax 8.48e-05%, nfe); Associated with TP63-related disorder.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1042354976 · 4 submitters · 9 linked conditions · AlphaMissense likely benign · very rare (popmax 8.48e-05%, nfe)

## 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 4 submitters, and is linked to TP63-related disorder.

*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.Ser41Phe |
| Coding change (HGVS c.) | c.122C>T |
| MANE Select transcript | [NM_003722](https://www.ncbi.nlm.nih.gov/nuccore/NM_003722) |
| dbSNP | [rs1042354976](https://www.ncbi.nlm.nih.gov/snp/rs1042354976/) |
| Variant type | single nucleotide variant |
| Location | chr3:189737799-189737799 (GRCh38) |
| ClinVar | [VCV2632741](https://www.ncbi.nlm.nih.gov/clinvar/variation/2632741/) |

**All HGVS expressions:** `LRG_428:g.146054C>T`, `LRG_428t1:c.122C>T`, `NC_000003.11:g.189455588C>T`, `NC_000003.12:g.189737799C>T`, `NG_007550.3:g.146054C>T`, `NM_001114978.2:c.122C>T`, `NM_001114979.2:c.122C>T`, `NM_001329144.2:c.122C>T`, `NM_001329148.2:c.122C>T`, `NM_001329964.2:c.116C>T`, `NM_003722.5:c.122C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2429)
- REVEL 0.757 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -8.221 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 6.013, GERP 1.99, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.9**. 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 0.85** across the covering region of the MANE Select transcript (189,631,516–189,808,439), spanning 176,923 bp. Chi-square p 0.031. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for TP63 (1,180 scored positions, the nearest 52 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,910 in the highest group · 1/1,614,030 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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 **41** lies in the 'transcription activation' region.

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.Ser41Phe falls in the transcription activation 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-08-21.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-12 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-09 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-21 |

## Associated conditions {#conditions}

[TP63-related disorder](https://sugi.bio/atlas/disease/tp63-related-disorder/), [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/), [premature ovarian failure 21](https://sugi.bio/atlas/disease/premature-ovarian-failure-21/).

**Reported phenotype names (ClinVar):** TP63-related disorder, ADULT syndrome, Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, Limb-mammary syndrome, Orofacial cleft 8, Premature ovarian failure 21, Rapp-Hodgkin syndrome, Split hand-foot malformation 4, TP63-Related Spectrum Disorders.

## 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 2632741). 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.*