Is TP63 p.Ser580Pro (c.1738T>C) pathogenic?

TP63 p.Ser580Pro (c.1738T>C) is classified Pathogenic in TP63 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2003-06-01). AlphaMissense: likely pathogenic (0.6538); Absent from gnomAD v4.1; Associated with Rapp-Hodgkin syndrome.

What condition is associated with TP63 p.Ser580Pro (c.1738T>C)?

TP63 p.Ser580Pro (c.1738T>C) is associated with Rapp-Hodgkin syndrome (ClinVar).

How common is TP63 p.Ser580Pro (c.1738T>C) in the general population?

TP63 p.Ser580Pro (c.1738T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TP63 p.Ser580Pro (c.1738T>C)?

AlphaMissense predicts likely pathogenic (score 0.6538) — an in-silico prediction, not a clinical call.

TP63 p.Ser580Pro

c.1738T>C · rs121908846 · VCV6545

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6538 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rapp-Hodgkin syndrome

Computational evidence

Protein change
AlphaMissense	0.6538	likely pathogenic ✓ concordant with ClinVar
REVEL	0.701	pathogenic-leaning
SaProt	LLR -13.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.1	GERP 2.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 26 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	26.2	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

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.Ser580Pro
Coding: c.1738T>C
MANE Select: NM_003722
dbSNP: rs121908846
Type: single nucleotide variant
Location: chr3:189890874 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 580: the sam domain; a UniProt-annotated variant site (in rhs)

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

Disease context

Rapp-Hodgkin syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TP63 p.Arg243Trp Pathogenic ★★ same condition
TP63 p.Arg318His Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg343Gln Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Arg343Trp Pathogenic ★★ same condition
TP63 p.Arg21His Uncertain significance ★★ ⚠ same condition
TP63 p.Arg37Gln Uncertain significance ★★ ⚠ same condition
TP63 p.Arg674His Uncertain significance ★★ same condition
TP63 p.Arg7Trp 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-ser580pro (accessed [today's date]).

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