Is TP63 p.Asp8fs (c.22_23del) pathogenic?

TP63 p.Asp8fs (c.2223del) is classified Uncertain significance in TP63 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-10). Ultra-rare (popmax 0.0131%, amr); Associated with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome.

How common is TP63 p.Asp8fs (c.22_23del) in the general population?

TP63 p.Asp8fs (c.22_23del) is ultra-rare (popmax 0.0131%, amr) (gnomAD).

TP63 p.Asp8fs

Q: What condition is associated with TP63 p.Asp8fs (c.22_23del)?

TP63 p.Asp8fs (c.22_23del) is associated with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, ADULT syndrome, Rapp-Hodgkin syndrome (ClinVar).

c.22_23del · VCV3892697

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, amr)

Conditions

ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.28	GERP -1.9
Overall
CADD	1.063	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0131% Admixed American · 2/15,288 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000907%

Overall 0.00131% 2/152,196 alleles · ultra-rare

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.Asp8fs
Coding: c.22_23del
MANE Select: NM_003722 · reported on NM_001329964
Type: Microsatellite
Location: chr3:189597199 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 8: the 'transcription activation' region

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

Disease context

ankyloblepharon-ectodermal defects-cleft lip/palate syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ADULT syndrome Rapp-Hodgkin syndrome limb-mammary syndrome ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 split hand-foot malformation 4 premature ovarian failure 21

Similar variants

TP63 c.1507+6_1507+7del Uncertain significance ★★ same condition
TP63 p.Ser612del Uncertain significance ★★ same condition
TP63 p.Ser560del Likely pathogenic ★ same condition
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

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-asp8fs (accessed [today's date]).

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