Is TP63 p.Ser389Phe (c.1166C>T) pathogenic?

TP63 p.Ser389Phe (c.1166C>T) is classified Uncertain significance in TP63 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-18). AlphaMissense: ambiguous (0.5367); Very rare (popmax 0.000763%, nfe); Associated with TP63-Related Spectrum Disorders.

What condition is associated with TP63 p.Ser389Phe (c.1166C>T)?

TP63 p.Ser389Phe (c.1166C>T) is associated with TP63-Related Spectrum Disorders (ClinVar).

How common is TP63 p.Ser389Phe (c.1166C>T) in the general population?

TP63 p.Ser389Phe (c.1166C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about TP63 p.Ser389Phe (c.1166C>T)?

AlphaMissense predicts ambiguous (score 0.5367) — an in-silico prediction, not a clinical call.

TP63 p.Ser389Phe

c.1166C>T · rs1560281511 · VCV2703834

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5367 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

TP63-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.5367	ambiguous
REVEL	0.69	pathogenic-leaning
SaProt	LLR -11.47	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	27.6	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 0.000763% European (non-Finnish) · 9/1,179,978 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,614,096 alleles · very rare exomes 9/1,461,770 · genomes 0/152,326 · joint denominator

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.Ser389Phe
Coding: c.1166C>T
MANE Select: NM_003722
dbSNP: rs1560281511
Type: single nucleotide variant
Location: chr3:189869360 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 389: the 'disordered' 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.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
TP63 p.His247Tyr 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-ser389phe (accessed [today's date]).

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