Is TP63 p.Thr451Ser (c.1352C>G) pathogenic?

TP63 p.Thr451Ser (c.1352C>G) is classified Conflicting classifications of pathogenicity in TP63 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0644); Rare (popmax 0.115%, mid); Associated with ADULT syndrome.

What condition is associated with TP63 p.Thr451Ser (c.1352C>G)?

TP63 p.Thr451Ser (c.1352C>G) is associated with ADULT syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, Rapp-Hodgkin syndrome (ClinVar).

How common is TP63 p.Thr451Ser (c.1352C>G) in the general population?

TP63 p.Thr451Ser (c.1352C>G) is rare (popmax 0.115%, mid) (gnomAD).

What do computational predictors say about TP63 p.Thr451Ser (c.1352C>G)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

TP63 p.Thr451Ser

c.1352C>G · rs747305746 · VCV1503085

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

ADULT syndrome

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.548	indeterminate
SaProt	LLR -5.26	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 4.9	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	19.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% Middle Eastern · 7/6,082 alleles

Filtering AF 0.054% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.00378% 61/1,613,894 alleles · rare exomes 56/1,461,728 · genomes 5/152,166 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	869
Remaining individualsnot grpmax-eligible	0.0064%	15,620
Admixed American	0.005%	20,000
European (non-Finnish)	0.00398%	25,106

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.Thr451Ser
Coding: c.1352C>G
MANE Select: NM_003722
dbSNP: rs747305746
Type: single nucleotide variant
Location: chr3:189886396 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 451: the 'disordered' region

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

Disease context

ADULT syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ankyloblepharon-ectodermal defects-cleft lip/palate syndrome Rapp-Hodgkin syndrome limb-mammary syndrome ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 split hand-foot malformation 4 orofacial cleft 8

Similar variants

TP63 p.Ala354Glu Likely pathogenic ★★ same condition
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.Arg319His 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-thr451ser (accessed [today's date]).

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