Is TP63 p.Pro428Ser (c.1282C>T) pathogenic?

TP63 p.Pro428Ser (c.1282C>T) is classified Uncertain significance in TP63 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-11). AlphaMissense: likely pathogenic (0.9561); Very rare (popmax 0.00333%, amr).

How common is TP63 p.Pro428Ser (c.1282C>T) in the general population?

TP63 p.Pro428Ser (c.1282C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about TP63 p.Pro428Ser (c.1282C>T)?

AlphaMissense predicts likely pathogenic (score 0.9561) — an in-silico prediction, not a clinical call.

TP63 p.Pro428Ser

c.1282C>T · VCV3370738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9561 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9561	likely pathogenic
REVEL	0.708	pathogenic-leaning
SaProt	LLR -9.36	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	25.9	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 0.00333% Admixed American · 2/60,024 alleles

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

Overall 0.000124% 2/1,614,146 alleles · very rare exomes 2/1,461,858 · genomes 0/152,288 · 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.Pro428Ser
Coding: c.1282C>T
MANE Select: NM_003722
Type: single nucleotide variant
Location: chr3:189872928 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 428: the 'oligomerization' region

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

Similar variants

TP63 p.Pro428Leu Likely pathogenic ★ same residue
TP63 p.Ala354Glu Likely pathogenic ★★ same type
TP63 p.Arg243Gln Pathogenic/Likely pathogenic ★★ same type
TP63 p.Arg243Trp Pathogenic ★★ same type
TP63 p.Arg266Gln Pathogenic/Likely pathogenic ★★ same type
TP63 p.Arg318Cys Pathogenic ★★ same type
TP63 p.Arg318His Pathogenic/Likely pathogenic ★★ same type
TP63 p.Arg319Cys Pathogenic/Likely pathogenic ★★ same type

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-pro428ser (accessed [today's date]).

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