Is TP63 p.Arg669Cys (c.2005C>T) pathogenic?

TP63 p.Arg669Cys (c.2005C>T) is classified Uncertain significance in TP63 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-12). AlphaMissense: likely pathogenic (0.749); Ultra-rare (popmax 0.0134%, eas); Associated with TP63-Related Spectrum Disorders.

What condition is associated with TP63 p.Arg669Cys (c.2005C>T)?

TP63 p.Arg669Cys (c.2005C>T) is associated with TP63-Related Spectrum Disorders (ClinVar).

How common is TP63 p.Arg669Cys (c.2005C>T) in the general population?

TP63 p.Arg669Cys (c.2005C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about TP63 p.Arg669Cys (c.2005C>T)?

AlphaMissense predicts likely pathogenic (score 0.749) — an in-silico prediction, not a clinical call.

TP63 p.Arg669Cys

c.2005C>T · rs143676789 · VCV1970534

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.749 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TP63-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.749	likely pathogenic
REVEL	0.532	indeterminate
SaProt	LLR -8.07	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	29.9	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 0.0134% East Asian · 6/44,868 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00062% 10/1,613,844 alleles · ultra-rare exomes 8/1,461,764 · genomes 2/152,080 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,478
South Asian	0.0022%	45,523
African / African-American	0.00134%	74,886
European (non-Finnish)	8.47e-05%	1,180,008

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.Arg669Cys
Coding: c.2005C>T
MANE Select: NM_003722
dbSNP: rs143676789
Type: single nucleotide variant
Location: chr3:189894464 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 669: a UniProt-annotated variant site (in pof21; results in increased transcriptional activation in luciferase reporter assays; affects oligomerization); a UniProt-annotated variant site (in pof21); a UniProt-annotated variant site (in lms); the 'transactivation inhibition' region

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

Disease context

TP63-Related Spectrum Disorders

Similar variants

TP63 p.Arg669His Likely benign ★ same residue
TP63 p.Arg318His Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Cys561Tyr Likely pathogenic ★★ same condition
TP63 p.Gly173Arg Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Gly173Asp Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Gly336Asp Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Gly557Val Pathogenic/Likely pathogenic ★★ same condition
TP63 p.His247Arg 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-arg669cys (accessed [today's date]).

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