Is TP63 p.Ser457Pro (c.1369T>C) pathogenic?

TP63 p.Ser457Pro (c.1369T>C) is classified Uncertain significance in TP63 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: likely benign (0.0791); Very rare (popmax 0.00833%, amr); Associated with TP63-Related Spectrum Disorders.

What condition is associated with TP63 p.Ser457Pro (c.1369T>C)?

TP63 p.Ser457Pro (c.1369T>C) is associated with TP63-Related Spectrum Disorders (ClinVar).

How common is TP63 p.Ser457Pro (c.1369T>C) in the general population?

TP63 p.Ser457Pro (c.1369T>C) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about TP63 p.Ser457Pro (c.1369T>C)?

AlphaMissense predicts likely benign (score 0.0791) — an in-silico prediction, not a clinical call.

TP63 p.Ser457Pro

c.1369T>C · rs577715207 · VCV3008116

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0791 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TP63-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.0791	likely benign
REVEL	0.453	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 0.39	GERP -2.1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	14.66	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 0.00833% Admixed American · 5/60,002 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000434% 7/1,614,014 alleles · very rare exomes 6/1,461,820 · genomes 1/152,194 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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.Ser457Pro
Coding: c.1369T>C
MANE Select: NM_003722
dbSNP: rs577715207
Type: single nucleotide variant
Location: chr3:189886413 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 457: the 'disordered' region

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

Disease context

TP63-Related Spectrum Disorders

Similar variants

TP63 p.Arg318His Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Cys561Tyr Likely pathogenic ★★ same condition
TP63 p.Gly173Arg Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Gly173Asp Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Gly336Asp Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Gly557Val Pathogenic/Likely pathogenic ★★ same condition
TP63 p.His247Arg Pathogenic ★★ same condition
TP63 p.His247Tyr 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-ser457pro (accessed [today's date]).

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