Is TP63 p.Pro289Ser (c.865C>T) pathogenic?

TP63 p.Pro289Ser (c.865C>T) is classified Uncertain significance in TP63 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-18). AlphaMissense: likely pathogenic (0.8374); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with TP63 p.Pro289Ser (c.865C>T)?

TP63 p.Pro289Ser (c.865C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TP63 p.Pro289Ser (c.865C>T) in the general population?

TP63 p.Pro289Ser (c.865C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about TP63 p.Pro289Ser (c.865C>T)?

AlphaMissense predicts likely pathogenic (score 0.8374) — an in-silico prediction, not a clinical call.

TP63 p.Pro289Ser

c.865C>T · rs757045273 · VCV1955396

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8374 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8374	likely pathogenic
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -11.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 63 bp · p 0.48 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00211% 34/1,613,888 alleles · ultra-rare exomes 32/1,461,792 · genomes 2/152,096 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.02%	5,000
European (non-Finnish)	0.00161%	62,104
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Pro289Ser
Coding: c.865C>T
MANE Select: NM_003722
dbSNP: rs757045273
Type: single nucleotide variant
Location: chr3:189866780 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 289: a β-strand; a DNA-binding region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TP63 p.Gln9Ter Likely pathogenic ★★ same condition
TP63 p.Arg376Cys Uncertain significance ★★ ⚠ same condition
TP63 p.Asn370Thr Uncertain significance ★★ ⚠ same condition
TP63 p.Gln439Lys Uncertain significance ★★ ⚠ same condition
TP63 p.Gly518Glu Uncertain significance ★★ same condition
TP63 p.Pro484Thr Uncertain significance ★★ ⚠ same condition
TP63 p.Thr144Met Uncertain significance ★★ ⚠ same condition
TP63 p.Gln380Ter 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-pro289ser (accessed [today's date]).

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