Is TP63 p.Arg338Cys (c.1012C>T) pathogenic?

TP63 p.Arg338Cys (c.1012C>T) is classified Likely pathogenic in TP63 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-01-17). AlphaMissense: likely pathogenic (0.9286); Very rare (popmax 0.000424%, nfe); Associated with ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3.

What condition is associated with TP63 p.Arg338Cys (c.1012C>T)?

TP63 p.Arg338Cys (c.1012C>T) is associated with ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (ClinVar).

How common is TP63 p.Arg338Cys (c.1012C>T) in the general population?

TP63 p.Arg338Cys (c.1012C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about TP63 p.Arg338Cys (c.1012C>T)?

AlphaMissense predicts likely pathogenic (score 0.9286) — an in-silico prediction, not a clinical call.

TP63 p.Arg338Cys

c.1012C>T · rs1404019220 · VCV1344645

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9286 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

Computational evidence

Protein change
AlphaMissense	0.9286	likely pathogenic ✓ concordant with ClinVar
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -13.35	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 4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 1,862 bp · p 2.1e-09 · regional, not allelic
Overall
CADD	29.8	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 0.000424% European (non-Finnish) · 5/1,179,992 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,074 alleles · very rare exomes 5/1,461,796 · genomes 0/152,278 · 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.Arg338Cys
Coding: c.1012C>T
MANE Select: NM_003722
dbSNP: rs1404019220
Type: single nucleotide variant
Location: chr3:189868599 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 338: a β-strand; a DNA-binding region

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

Disease context

ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TP63 p.Arg338His Uncertain significance ★ ⚠ same residue
TP63 p.Arg338= Likely benign ★ 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

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-arg338cys (accessed [today's date]).

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