Is TP63 p.Pro528Arg (c.1583C>G) pathogenic?

TP63 p.Pro528Arg (c.1583C>G) is classified Uncertain significance in TP63 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-30). AlphaMissense: likely benign (0.2352); Very rare (popmax 0.000254%, nfe); Associated with TP63-related disorder.

What condition is associated with TP63 p.Pro528Arg (c.1583C>G)?

TP63 p.Pro528Arg (c.1583C>G) is associated with TP63-related disorder (ClinVar).

How common is TP63 p.Pro528Arg (c.1583C>G) in the general population?

TP63 p.Pro528Arg (c.1583C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about TP63 p.Pro528Arg (c.1583C>G)?

AlphaMissense predicts likely benign (score 0.2352) — an in-silico prediction, not a clinical call.

TP63 p.Pro528Arg

c.1583C>G · rs761041436 · VCV2631266

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TP63-related disorder

Computational evidence

Protein change
AlphaMissense	0.2352	likely benign
REVEL	0.494	indeterminate
SaProt	LLR -8.87	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	23.5	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 0.000254% European (non-Finnish) · 3/1,180,010 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

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

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.Pro528Arg
Coding: c.1583C>G
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 disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TP63 p.Pro528Gln Uncertain significance ★★ ⚠ same residue
TP63 p.Pro528Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
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.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-pro528arg (accessed [today's date]).

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