Is TP63 p.Ser458= (c.1374A>G) pathogenic?

TP63 p.Ser458= (c.1374A>G) is classified Conflicting classifications of pathogenicity in TP63 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-18). Very rare (popmax 0.00203%, nfe); Associated with orofacial cleft 8.

What condition is associated with TP63 p.Ser458= (c.1374A>G)?

TP63 p.Ser458= (c.1374A>G) is associated with orofacial cleft 8, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (ClinVar).

How common is TP63 p.Ser458= (c.1374A>G) in the general population?

TP63 p.Ser458= (c.1374A>G) is very rare (popmax 0.00203%, nfe) (gnomAD).

TP63 p.Ser458=

c.1374A>G · rs141794685 · VCV344387

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Conditions

orofacial cleft 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.9	GERP -5.7
Overall
CADD	1.911	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00203% European (non-Finnish) · 24/1,180,018 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00149% 24/1,614,028 alleles · very rare exomes 18/1,461,830 · genomes 6/152,198 · 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.Ser458=
Coding: c.1374A>G
MANE Select: NM_003722
dbSNP: rs141794685
Type: single nucleotide variant
Location: chr3:189886418 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 458: the 'disordered' region

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

Disease context

orofacial cleft 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

Similar variants

TP63 p.Ser458Pro Uncertain significance ★ ⚠ 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.Arg318His Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg319Cys Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg343Gln 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-ser458 (accessed [today's date]).

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