Is TP63 p.Met665Arg (c.1994T>G) pathogenic?

TP63 p.Met665Arg (c.1994T>G) is classified Uncertain significance in TP63 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely pathogenic (0.6392); Absent from gnomAD v4.1; Associated with orofacial cleft 8.

What condition is associated with TP63 p.Met665Arg (c.1994T>G)?

TP63 p.Met665Arg (c.1994T>G) is associated with orofacial cleft 8, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (ClinVar).

How common is TP63 p.Met665Arg (c.1994T>G) in the general population?

TP63 p.Met665Arg (c.1994T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TP63 p.Met665Arg (c.1994T>G)?

AlphaMissense predicts likely pathogenic (score 0.6392) — an in-silico prediction, not a clinical call.

TP63 p.Met665Arg

c.1994T>G · rs886058223 · VCV344391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6392 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

orofacial cleft 8

Computational evidence

Protein change
AlphaMissense	0.6392	likely pathogenic
REVEL	0.464	indeterminate
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	26.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TP63
Protein: p.Met665Arg
Coding: c.1994T>G
MANE Select: NM_003722
dbSNP: rs886058223
Type: single nucleotide variant
Location: chr3:189894453 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 665: a UniProt-annotated variant site (in pof21; results in increased transcriptional activation in luciferase reporter assays; affects oligomerization); a UniProt-annotated variant site (in pof21); a UniProt-annotated variant site (in lms); the 'transactivation inhibition' region

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-met665arg (accessed [today's date]).

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