Is TP63 p.Pro133= (c.399C>T) pathogenic?

TP63 p.Pro133= (c.399C>T) is classified Benign/Likely benign in TP63 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-24). Rare (popmax 0.6%, afr); Associated with TP63-Related Spectrum Disorders.

What condition is associated with TP63 p.Pro133= (c.399C>T)?

TP63 p.Pro133= (c.399C>T) is associated with TP63-Related Spectrum Disorders, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, orofacial cleft 8 (ClinVar).

How common is TP63 p.Pro133= (c.399C>T) in the general population?

TP63 p.Pro133= (c.399C>T) is rare (popmax 0.6%, afr) (gnomAD).

TP63 p.Pro133=

c.399C>T · rs145730343 · VCV284618

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.6%, afr)

Conditions

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 -1.4	GERP -5.3
Overall
CADD	6.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.6% African / African-American · 450/75,056 alleles

Filtering AF 0.554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.536%

Overall 0.0302% 487/1,614,232 alleles · rare exomes 213/1,461,894 · genomes 274/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.6%	167
Remaining individualsnot grpmax-eligible	0.032%	3,125
Admixed American	0.0217%	4,618
South Asian	0.0011%	91,082
European (non-Finnish)	0.000254%	393,349

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.Pro133=
Coding: c.399C>T
MANE Select: NM_003722
dbSNP: rs145730343
Type: single nucleotide variant
Location: chr3:189808346 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 133: the 'disordered' region

Full TP63 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TP63-Related Spectrum Disorders

Also linked: ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 orofacial cleft 8

Similar variants

TP63 p.Arg243Gln Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg243Trp Pathogenic ★★ same condition
TP63 p.Arg266Gln Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg318Cys Pathogenic ★★ same condition
TP63 p.Arg318His Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg319Cys Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg343Gln Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg343Trp 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-pro133 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown