TP63 p.Pro653=
c.1959A>G · VCV3612842
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0659%, mid)
Conditions
1
TP63-Related Spectrum Disorders
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -0.51 | GERP -3.5 |
| Overall | ||
| CADD | 7.472 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0659%
Middle Eastern · 4/6,074 alleles
Filtering AF
0.0224%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0135%
Overall
0.000496%
8/1,612,894 alleles · ultra-rare
exomes 7/1,461,824 · genomes 1/151,070 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0659% | 1,518 |
| Remaining individualsnot grpmax-eligible | 0.0048% | 20,822 |
| European (non-Finnish) | 8.48e-05% | 1,179,760 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- TP63
- Protein
- p.Pro653=
- Coding
- c.1959A>G
- MANE Select
- NM_003722
- Type
- single nucleotide variant
- Location
- chr3:189894418 (GRCh38)
- Gene constraint
- LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
- Structure
- AlphaFold pLDDT 63.70 · 26 PDB
- Residue 653
- a UniProt-annotated variant site (in pof21; results in increased transcriptional activation in luciferase reporter assays; affects oligomerization); a UniProt-annotated variant site (in pof21); a UniProt-annotated variant site (in lms); the 'transactivation inhibition' region
Disease context
TP63-Related Spectrum Disorders
Similar variants
- TP63 p.Arg318His Pathogenic/Likely pathogenic ★★ same condition
- TP63 p.Cys561Tyr Likely pathogenic ★★ same condition
- TP63 p.Gly173Arg Pathogenic/Likely pathogenic ★★ same condition
- TP63 p.Gly173Asp Pathogenic/Likely pathogenic ★★ same condition
- TP63 p.Gly336Asp Pathogenic/Likely pathogenic ★★ same condition
- TP63 p.Gly557Val Pathogenic/Likely pathogenic ★★ same condition
- TP63 p.His247Arg Pathogenic ★★ same condition
- TP63 p.His247Tyr Pathogenic/Likely pathogenic ★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tp63-p-pro653 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown