Is TP63 p.Ala554Val (c.1661C>T) pathogenic?

TP63 p.Ala554Val (c.1661C>T) is classified Conflicting classifications of pathogenicity in TP63 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.1044); Very rare (popmax 0.0078%, nfe); Associated with TP63-Related Spectrum Disorders.

What condition is associated with TP63 p.Ala554Val (c.1661C>T)?

TP63 p.Ala554Val (c.1661C>T) is associated with TP63-Related Spectrum Disorders, ADULT syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (ClinVar).

How common is TP63 p.Ala554Val (c.1661C>T) in the general population?

TP63 p.Ala554Val (c.1661C>T) is very rare (popmax 0.0078%, nfe) (gnomAD).

What do computational predictors say about TP63 p.Ala554Val (c.1661C>T)?

AlphaMissense predicts likely benign (score 0.1044) — an in-silico prediction, not a clinical call.

TP63 p.Ala554Val

c.1661C>T · rs747808524 · VCV2721206

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1044 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0078%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TP63-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.1044	likely benign
REVEL	0.35	indeterminate
SaProt	LLR -7.75	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 6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	23.2	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 0.0078% European (non-Finnish) · 92/1,179,948 alleles

Filtering AF 0.00648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.006%

Overall 0.00589% 95/1,613,880 alleles · very rare exomes 91/1,461,734 · genomes 4/152,146 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0078%	12,826
East Asian	0.00223%	44,890
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00134%	74,892

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.Ala554Val
Coding: c.1661C>T
MANE Select: NM_003722
dbSNP: rs747808524
Type: single nucleotide variant
Location: chr3:189890797 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 554: the sam domain; an α-helix

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 premature ovarian failure 21

Similar variants

TP63 p.Ala554= Likely benign ★ 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-ala554val (accessed [today's date]).

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