Is TP63 p.Ser622Arg (c.1866T>G) pathogenic?

TP63 p.Ser622Arg (c.1866T>G) is classified Uncertain significance in TP63 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely pathogenic (0.7184); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with TP63 p.Ser622Arg (c.1866T>G)?

TP63 p.Ser622Arg (c.1866T>G) is associated with Inborn genetic diseases (ClinVar).

How common is TP63 p.Ser622Arg (c.1866T>G) in the general population?

TP63 p.Ser622Arg (c.1866T>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TP63 p.Ser622Arg (c.1866T>G)?

AlphaMissense predicts likely pathogenic (score 0.7184) — an in-silico prediction, not a clinical call.

TP63 p.Ser622Arg

c.1866T>G · VCV4633439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7184 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7184	likely pathogenic
REVEL	0.496	indeterminate
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.2	GERP -5.6
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	17.83	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 0.00167% Admixed American · 1/59,988 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,890 alleles · very rare exomes 3/1,461,878 · genomes 0/152,012 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,988
European (non-Finnish)	0.000169%	589,988

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.Ser622Arg
Coding: c.1866T>G
MANE Select: NM_003722
Type: single nucleotide variant
Location: chr3:189894325 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 622: an α-helix; 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); the 'transactivation inhibition' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TP63 p.Gln9Ter Likely pathogenic ★★ same condition
TP63 p.Arg376Cys Uncertain significance ★★ ⚠ same condition
TP63 p.Asn370Thr Uncertain significance ★★ ⚠ same condition
TP63 p.Gln439Lys Uncertain significance ★★ ⚠ same condition
TP63 p.Gly518Glu Uncertain significance ★★ same condition
TP63 p.Pro289Ser Uncertain significance ★★ ⚠ same condition
TP63 p.Pro484Thr Uncertain significance ★★ ⚠ same condition
TP63 p.Thr144Met Uncertain significance ★★ ⚠ 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-ser622arg (accessed [today's date]).

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