Is TP63 p.Pro348Ala (c.1042C>G) pathogenic?

TP63 p.Pro348Ala (c.1042C>G) is classified Uncertain significance in TP63 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-15). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with TP63-Related Spectrum Disorders.

What condition is associated with TP63 p.Pro348Ala (c.1042C>G)?

TP63 p.Pro348Ala (c.1042C>G) is associated with TP63-Related Spectrum Disorders (ClinVar).

How common is TP63 p.Pro348Ala (c.1042C>G) in the general population?

TP63 p.Pro348Ala (c.1042C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TP63 p.Pro348Ala (c.1042C>G)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

TP63 p.Pro348Ala

c.1042C>G · rs1577147850 · VCV659864

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TP63-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 6% in TP63
REVEL	0.852	moderately pathogenic-leaning
SaProt	LLR -13.59	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 7.7	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	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

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.Pro348Ala
Coding: c.1042C>G
MANE Select: NM_003722
dbSNP: rs1577147850
Type: single nucleotide variant
Location: chr3:189868629 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 348: an α-helix; a DNA-binding region; a UniProt-annotated variant site (in eec3)

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

Disease context

TP63-Related Spectrum Disorders

Similar variants

TP63 p.Pro348Leu Uncertain significance ★ ⚠ same residue
TP63 p.Pro348= Likely benign ★ same residue
TP63 p.Pro348Ser Likely pathogenic ★ same residue
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

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-pro348ala (accessed [today's date]).

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