Is TP63 p.Arg226= (c.678C>T) pathogenic?

TP63 p.Arg226= (c.678C>T) is classified Conflicting classifications of pathogenicity in TP63 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-12-24). Ultra-rare (popmax 0.058%, nfe); Associated with TP63-Related Spectrum Disorders.

What condition is associated with TP63 p.Arg226= (c.678C>T)?

TP63 p.Arg226= (c.678C>T) is associated with TP63-Related Spectrum Disorders, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, orofacial cleft 8 (ClinVar).

How common is TP63 p.Arg226= (c.678C>T) in the general population?

TP63 p.Arg226= (c.678C>T) is ultra-rare (popmax 0.058%, nfe) (gnomAD).

TP63 p.Arg226=

c.678C>T · rs61732782 · VCV497709

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.058%, nfe)

Conditions

TP63-Related Spectrum Disorders

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 -5.1	GERP -3.9
Overall
CADD	8.271	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.058% European (non-Finnish) · 685/1,180,034 alleles

Filtering AF 0.0544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.053%

Overall 0.0461% 744/1,614,022 alleles · ultra-rare exomes 695/1,461,868 · genomes 49/152,154 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.058%	1,723
Remaining individualsnot grpmax-eligible	0.048%	2,083
Admixed American	0.0217%	4,615
African / African-American	0.0174%	5,763
East Asian	0.00223%	44,876
South Asian	0.0022%	45,540

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.Arg226=
Coding: c.678C>T
MANE Select: NM_003722
dbSNP: rs61732782
Type: single nucleotide variant
Location: chr3:189864330 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 226: a DNA-binding region; a β-strand

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

Disease context

TP63-Related Spectrum Disorders

Also linked: ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 orofacial cleft 8

Similar variants

TP63 p.Arg226His 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-arg226 (accessed [today's date]).

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