Is TP63 p.Ala489Thr (c.1465G>A) pathogenic?

TP63 p.Ala489Thr (c.1465G>A) is classified Conflicting classifications of pathogenicity in TP63 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-06). AlphaMissense: likely benign (0.072); Ultra-rare (popmax 0.0626%, sas); Associated with orofacial cleft 8.

What condition is associated with TP63 p.Ala489Thr (c.1465G>A)?

TP63 p.Ala489Thr (c.1465G>A) is associated with orofacial cleft 8, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (ClinVar).

How common is TP63 p.Ala489Thr (c.1465G>A) in the general population?

TP63 p.Ala489Thr (c.1465G>A) is ultra-rare (popmax 0.0626%, sas) (gnomAD).

What do computational predictors say about TP63 p.Ala489Thr (c.1465G>A)?

AlphaMissense predicts likely benign (score 0.072) — an in-silico prediction, not a clinical call.

TP63 p.Ala489Thr

c.1465G>A · rs138832017 · VCV903553

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.072 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0626%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

orofacial cleft 8

Computational evidence

Protein change
AlphaMissense	0.072	likely benign
REVEL	0.436	indeterminate
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 1, phastCons 0.99
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	17.08	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 0.0626% South Asian · 57/91,066 alleles

Filtering AF 0.0496% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0449%

Overall 0.00502% 81/1,613,888 alleles · ultra-rare exomes 73/1,461,816 · genomes 8/152,072 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0626%	1,598
Middle Eastern	0.0329%	3,041
Remaining individualsnot grpmax-eligible	0.0064%	15,620
East Asian	0.00223%	44,866
Admixed American	0.00167%	59,978
African / African-American	0.00134%	74,900
European (non-Finnish)	0.00127%	78,666

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.Ala489Thr
Coding: c.1465G>A
MANE Select: NM_003722
dbSNP: rs138832017
Type: single nucleotide variant
Location: chr3:189886509 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB

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

Disease context

orofacial cleft 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

Similar variants

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.Arg343Gln Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg343Trp 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-ala489thr (accessed [today's date]).

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