Is TP63 p.Pro528Gln (c.1583C>A) pathogenic?

TP63 p.Pro528Gln (c.1583C>A) is classified Uncertain significance in TP63 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-10). AlphaMissense: likely benign (0.082); Very rare (popmax 0.00333%, amr); Associated with TP63-Related Spectrum Disorders.

What condition is associated with TP63 p.Pro528Gln (c.1583C>A)?

TP63 p.Pro528Gln (c.1583C>A) is associated with TP63-Related Spectrum Disorders, ADULT syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (ClinVar).

How common is TP63 p.Pro528Gln (c.1583C>A) in the general population?

TP63 p.Pro528Gln (c.1583C>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about TP63 p.Pro528Gln (c.1583C>A)?

AlphaMissense predicts likely benign (score 0.082) — an in-silico prediction, not a clinical call.

TP63 p.Pro528Gln

c.1583C>A · rs761041436 · VCV1385690

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.082 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TP63-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.082	likely benign
REVEL	0.461	indeterminate
SaProt	LLR -7.86	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 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,010 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000186% 3/1,614,018 alleles · very rare exomes 2/1,461,808 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,005
European (non-Finnish)	8.47e-05%	1,180,011

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.Pro528Gln
Coding: c.1583C>A
MANE Select: NM_003722
dbSNP: rs761041436
Type: single nucleotide variant
Location: chr3:189889415 (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

TP63-Related Spectrum Disorders

Also linked: ADULT syndrome ankyloblepharon-ectodermal defects-cleft lip/palate syndrome Rapp-Hodgkin syndrome limb-mammary syndrome ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 split hand-foot malformation 4 orofacial cleft 8 premature ovarian failure 21

Similar variants

TP63 p.Pro528Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TP63 p.Pro528Arg Uncertain significance ★★ ⚠ same residue
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

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-pro528gln (accessed [today's date]).

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