Is TP63 p.Ser365= (c.1095G>A) pathogenic?

TP63 p.Ser365= (c.1095G>A) is classified Likely benign in TP63 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-01). Ultra-rare (popmax 0.0329%, mid); Associated with ADULT syndrome.

What condition is associated with TP63 p.Ser365= (c.1095G>A)?

TP63 p.Ser365= (c.1095G>A) is associated with ADULT syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, Rapp-Hodgkin syndrome (ClinVar).

How common is TP63 p.Ser365= (c.1095G>A) in the general population?

TP63 p.Ser365= (c.1095G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

TP63 p.Ser365=

c.1095G>A · rs748609799 · VCV1452532

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

ADULT syndrome

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 1.5	GERP 0.19, phastCons 1
Overall
CADD	13.49	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00446% 72/1,613,912 alleles · ultra-rare exomes 64/1,461,810 · genomes 8/152,102 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
South Asian	0.0143%	7,006
Admixed American	0.0117%	8,570
Remaining individualsnot grpmax-eligible	0.0048%	20,826
European (non-Finnish)	0.0039%	25,652
Finnishnot grpmax-eligible	0.00156%	64,020

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.Ser365=
Coding: c.1095G>A
MANE Select: NM_003722
dbSNP: rs748609799
Type: single nucleotide variant
Location: chr3:189868682 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 365: an α-helix; the 'disordered' region; the 'interaction with hipk2' region

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

Disease context

ADULT syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 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.Ser365Leu Uncertain significance ★ ⚠ same residue
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

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-ser365 (accessed [today's date]).

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