Is TP63 p.Cys345Phe (c.1034G>T) pathogenic?

TP63 p.Cys345Phe (c.1034G>T) is classified Uncertain significance in TP63 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-23). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with TP63-related disorder.

What condition is associated with TP63 p.Cys345Phe (c.1034G>T)?

TP63 p.Cys345Phe (c.1034G>T) is associated with TP63-related disorder (ClinVar).

How common is TP63 p.Cys345Phe (c.1034G>T) in the general population?

TP63 p.Cys345Phe (c.1034G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TP63 p.Cys345Phe (c.1034G>T)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

TP63 p.Cys345Phe

c.1034G>T · rs2108806372 · VCV2635464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TP63-related disorder

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 6% in TP63
REVEL	0.953	strongly pathogenic-leaning
SaProt	LLR -13.41	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 1,862 bp · p 2.1e-09 · regional, not allelic
Overall
CADD	29.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TP63
Protein: p.Cys345Phe
Coding: c.1034G>T
MANE Select: NM_003722
dbSNP: rs2108806372
Type: single nucleotide variant
Location: chr3:189868621 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 345: a DNA-binding region; a UniProt-annotated variant site (in eec3; abolishes transcription activation)

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.Cys345Arg Pathogenic 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
TP63 p.Arg337Gln 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-cys345phe (accessed [today's date]).

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