Is TP63 p.Pro511Thr (c.1531C>A) pathogenic?

TP63 p.Pro511Thr (c.1531C>A) is classified Benign/Likely benign in TP63 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.0744); Low-frequency (popmax 1.96%, mid); Associated with ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3.

What condition is associated with TP63 p.Pro511Thr (c.1531C>A)?

TP63 p.Pro511Thr (c.1531C>A) is associated with ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, ADULT syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (ClinVar).

How common is TP63 p.Pro511Thr (c.1531C>A) in the general population?

TP63 p.Pro511Thr (c.1531C>A) is low-frequency (popmax 1.96%, mid) (gnomAD).

What do computational predictors say about TP63 p.Pro511Thr (c.1531C>A)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

TP63 p.Pro511Thr

c.1531C>A · rs148076109 · VCV286990

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.96%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -6.65	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.96% Middle Eastern · 119/6,062 alleles

Filtering AF 1.68% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.57%

Overall 0.332% 5,353/1,614,168 alleles · low-frequency exomes 4,890/1,461,876 · genomes 463/152,292 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.96%	51
Admixed American	0.555%	180
Remaining individualsnot grpmax-eligible	0.402%	249
European (non-Finnish)	0.37%	270
South Asian	0.157%	637
Finnishnot grpmax-eligible	0.0984%	1,017
African / African-American	0.0853%	1,172
Ashkenazi Jewishnot grpmax-eligible	0.0473%	2,115
East Asian	0.00223%	44,868

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.Pro511Thr
Coding: c.1531C>A
MANE Select: NM_003722
dbSNP: rs148076109
Type: single nucleotide variant
Location: chr3:189889363 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB

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

Disease context

ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ADULT syndrome ankyloblepharon-ectodermal defects-cleft lip/palate syndrome Rapp-Hodgkin syndrome limb-mammary syndrome split hand-foot malformation 4 orofacial cleft 8

Similar variants

TP63 p.Ala354Glu Likely pathogenic ★★ same condition
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.Arg319His 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-pro511thr (accessed [today's date]).

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