Is TP63 p.Pro17Arg (c.50C>G) pathogenic?

TP63 p.Pro17Arg (c.50C>G) is classified Uncertain significance in TP63 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-13). AlphaMissense: likely benign (0.0801); Very rare (popmax 0.00535%, afr); Associated with TP63-Related Spectrum Disorders.

What condition is associated with TP63 p.Pro17Arg (c.50C>G)?

TP63 p.Pro17Arg (c.50C>G) is associated with TP63-Related Spectrum Disorders, ADULT syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (ClinVar).

How common is TP63 p.Pro17Arg (c.50C>G) in the general population?

TP63 p.Pro17Arg (c.50C>G) is very rare (popmax 0.00535%, afr) (gnomAD).

What do computational predictors say about TP63 p.Pro17Arg (c.50C>G)?

AlphaMissense predicts likely benign (score 0.0801) — an in-silico prediction, not a clinical call.

TP63 p.Pro17Arg

c.50C>G · rs1408730457 · VCV1421645

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0801 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TP63-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.0801	likely benign
REVEL	0.511	indeterminate
SaProt	LLR -6.33	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 4.1	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 177 kb · p 0.031 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00535% African / African-American · 4/74,824 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,612,768 alleles · very rare exomes 1/1,460,656 · genomes 4/152,112 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,706
South Asian	0.0011%	91,064

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.Pro17Arg
Coding: c.50C>G
MANE Select: NM_003722
dbSNP: rs1408730457
Type: single nucleotide variant
Location: chr3:189631565 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 17: the 'transcription activation' region

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-pro17arg (accessed [today's date]).

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