Is TP63 p.Ala596= (c.1788G>A) pathogenic?

TP63 p.Ala596= (c.1788G>A) is classified Benign/Likely benign in TP63 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-01). Rare (popmax 0.563%, afr); Associated with TP63-Related Spectrum Disorders.

What condition is associated with TP63 p.Ala596= (c.1788G>A)?

TP63 p.Ala596= (c.1788G>A) is associated with TP63-Related Spectrum Disorders, ADULT syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (ClinVar).

How common is TP63 p.Ala596= (c.1788G>A) in the general population?

TP63 p.Ala596= (c.1788G>A) is rare (popmax 0.563%, afr) (gnomAD).

TP63 p.Ala596=

c.1788G>A · rs148577576 · VCV707020

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.563%, afr)

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 -0.5	GERP -5.1, phastCons 0.015
Overall
CADD	6.913	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.563% African / African-American · 422/74,976 alleles

Filtering AF 0.518% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.501%

Overall 0.0328% 529/1,613,984 alleles · rare exomes 277/1,461,860 · genomes 252/152,124 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.563%	178
Admixed American	0.05%	2,000
Remaining individualsnot grpmax-eligible	0.0384%	2,604
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00424%	23,600
South Asian	0.0022%	45,532

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.Ala596=
Coding: c.1788G>A
MANE Select: NM_003722
dbSNP: rs148577576
Type: single nucleotide variant
Location: chr3:189894247 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 596: the sam domain; an α-helix; a UniProt-annotated variant site (in pof21; results in increased transcriptional activation in luciferase reporter assays; affects oligomerization)

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

Disease context

TP63-Related Spectrum Disorders

Also linked: ADULT syndrome ankyloblepharon-ectodermal defects-cleft lip/palate syndrome Rapp-Hodgkin syndrome limb-mammary syndrome ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 split hand-foot malformation 4 orofacial cleft 8

Similar variants

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
TP63 p.Arg318His Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg319Cys Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg319His 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-ala596 (accessed [today's date]).

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