Is TP63 p.Arg243Gln (c.728G>A) pathogenic?

TP63 p.Arg243Gln (c.728G>A) is classified Pathogenic/Likely pathogenic in TP63 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.998); Very rare (popmax 0.000339%, nfe); Associated with TP63-related disorder.

What condition is associated with TP63 p.Arg243Gln (c.728G>A)?

TP63 p.Arg243Gln (c.728G>A) is associated with TP63-related disorder, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, split hand-foot malformation 4 (ClinVar).

How common is TP63 p.Arg243Gln (c.728G>A) in the general population?

TP63 p.Arg243Gln (c.728G>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about TP63 p.Arg243Gln (c.728G>A)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

TP63 p.Arg243Gln

c.728G>A · rs121908836 · VCV6528

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TP63-related disorder

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic ✓ concordant with ClinVar
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -14.41	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 0.44	unconstrained · MANE · 58 kb · p 2.4e-11 · regional, not allelic
Overall
CADD	32.0	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 0.000339% European (non-Finnish) · 4/1,179,900 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,792 alleles · very rare exomes 2/1,461,716 · genomes 2/152,076 · 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.Arg243Gln
Coding: c.728G>A
MANE Select: NM_003722
dbSNP: rs121908836
Type: single nucleotide variant
Location: chr3:189864380 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 243: 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

Also linked: ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 split hand-foot malformation 4

Similar variants

TP63 p.Arg243Trp Pathogenic ★★ same residue
TP63 p.Ala354Glu Likely 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
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-arg243gln (accessed [today's date]).

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