Is TP53 p.Cys176Arg (c.526T>C) pathogenic?

TP53 p.Cys176Arg (c.526T>C) is classified Conflicting classifications of pathogenicity in TP53 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-03). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with breast neoplasm.

What condition is associated with TP53 p.Cys176Arg (c.526T>C)?

TP53 p.Cys176Arg (c.526T>C) is associated with breast neoplasm, hereditary neoplastic syndrome, Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Cys176Arg (c.526T>C) in the general population?

TP53 p.Cys176Arg (c.526T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TP53 p.Cys176Arg (c.526T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

TP53 p.Cys176Arg

c.526T>C · rs967461896 · VCV376573

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,100)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

breast neoplasm

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 1% in TP53
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -14.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	27.2	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

No allele count reported in gnomAD v4.1 (AN 1,614,100). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TP53
Protein: p.Cys176Arg
Coding: c.526T>C
MANE Select: NM_000546
dbSNP: rs967461896
Type: single nucleotide variant
Location: chr17:7675086 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 176: a DNA-binding region; the 'interaction with axin1' region; an α-helix; the 'interaction with ccar2' region; a binding site; a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); the 'interaction with hipk1' region; the 'required for interaction with znf385a' region; the 'required for interaction with fbxo42' region

Full TP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

breast neoplasm — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome Li-Fraumeni syndrome ovarian neoplasm

Similar variants

TP53 p.Cys176Phe Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Cys176Ter Pathogenic ★★ same residue
TP53 p.Cys176Tyr Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Cys176Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Cys176Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Cys176Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Cys176= Likely benign ★ same residue
TP53 p.Cys176del Uncertain significance ★ same residue

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/tp53-p-cys176arg (accessed [today's date]).

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