Is TP73 p.Pro486Arg (c.1457C>G) pathogenic?

TP73 p.Pro486Arg (c.1457C>G) is classified Uncertain significance in TP73 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-04). AlphaMissense: likely benign (0.294); Ultra-rare (popmax 0.0245%, eas); Associated with Inborn genetic diseases.

What condition is associated with TP73 p.Pro486Arg (c.1457C>G)?

TP73 p.Pro486Arg (c.1457C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TP73 p.Pro486Arg (c.1457C>G) in the general population?

TP73 p.Pro486Arg (c.1457C>G) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about TP73 p.Pro486Arg (c.1457C>G)?

AlphaMissense predicts likely benign (score 0.294) — an in-silico prediction, not a clinical call.

TP73 p.Pro486Arg

c.1457C>G · VCV3460406

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.294 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.294	likely benign
REVEL	0.658	pathogenic-leaning
SaProt	LLR -8.19	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 0.95
Regional constraint	o/e 0.87	unconstrained · MANE · 5,880 bp · p 0.0021 · regional, not allelic
Overall
CADD	25.1	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 0.0245% East Asian · 11/44,882 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00347% 56/1,612,178 alleles · ultra-rare exomes 55/1,459,952 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,080
European (non-Finnish)	0.00373%	26,812
Remaining individualsnot grpmax-eligible	0.0016%	62,430

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: TP73
Protein: p.Pro486Arg
Coding: c.1457C>G
MANE Select: NM_005427
Type: single nucleotide variant
Location: chr1:3731038 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI 0.29 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.25 · 28 PDB
Residue 486: the sam domain; a UniProt-annotated variant site (in cild47)

Full TP73 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

TP73 p.Pro486Leu Uncertain significance ★ ⚠ same residue
TP73 p.Gly451Arg Uncertain significance ★★ ⚠ same condition
TP73 p.Ala100Thr Uncertain significance ★ ⚠ same condition
TP73 p.Ala112Val Uncertain significance ★ ⚠ same condition
TP73 p.Ala156Thr Uncertain significance ★ ⚠ same condition
TP73 p.Ala320Thr Uncertain significance ★ ⚠ same condition
TP73 p.Ala441Pro Uncertain significance ★ ⚠ same condition
TP73 p.Ala441Thr 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/tp73-p-pro486arg (accessed [today's date]).

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