Is TP53 p.Arg175Cys (c.523C>T) pathogenic?

TP53 p.Arg175Cys (c.523C>T) is classified Uncertain significance in TP53 (ClinVar, Expert panel, 14 submitters; last evaluated 2026-01-06). AlphaMissense: likely pathogenic (0.9186); Very rare (popmax 0.00329%, sas); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Arg175Cys (c.523C>T)?

TP53 p.Arg175Cys (c.523C>T) is associated with Li-Fraumeni syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is TP53 p.Arg175Cys (c.523C>T) in the general population?

TP53 p.Arg175Cys (c.523C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

How is Li-Fraumeni syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TP53 p.Arg175Cys (c.523C>T)?

AlphaMissense predicts likely pathogenic (score 0.9186) — an in-silico prediction, not a clinical call.

TP53 p.Arg175Cys

c.523C>T · rs138729528 · VCV245851

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

Uncertain Significance for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):

PP4_Moderate PP3_Moderate PM2_Supporting PS4_Moderate PM1 BS2_Moderate BS3_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.523C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cystindine at amino acid 175 (p.Arg175Cys). This variant has been reported in 4 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2 total point meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMIDs: 40540701, 31119730; Internal lab contributors). This variant has an allele frequency of 0.00003293 (3/91090 alleles) in the South Asian population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Computational predictor scores (BayesDel = 0.5443; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors: Ambry). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: Invitae). Although this variant meets the criteria to be classified as Likely Pathogenic the VCEP has overridden the classification to variant of uncertain clinical significance due to ambiguous clinical data: PS4_Moderate, PM2_Supporting, BS3_Supporting, PM1, PP3_Moderate, BS2_Moderate, PP4_Moderate. (Bayesian Points: 6; VCEP specifications version 2.4)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9186	likely pathogenic
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -14.82	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 9.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,090 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000681% 11/1,614,206 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,363
Finnishnot grpmax-eligible	0.00312%	32,015
African / African-American	0.00266%	37,528
European (non-Finnish)	0.000339%	295,011

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: TP53
Protein: p.Arg175Cys
Coding: c.523C>T
MANE Select: NM_000546
dbSNP: rs138729528
Type: single nucleotide variant
Location: chr17:7675089 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 175: a DNA-binding region; the 'interaction with axin1' region; an α-helix; the 'interaction with ccar2' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation; does not induce snai1 degradation; reduces interaction with znf385a); a UniProt-annotated variant site (in a sporadic cancer; 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

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

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 1 hereditary neoplastic syndrome ovarian neoplasm

For Li-Fraumeni syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

TP53 p.Arg175Gly Pathogenic ★★★ same residue
TP53 p.Arg175His Pathogenic ★★★ same residue
TP53 p.Arg175Leu Likely pathogenic ★★★ same residue
TP53 p.Arg175= Benign/Likely benign ★★ same residue
TP53 p.Arg175Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 c.375+5G>A Likely pathogenic ★★★ same condition
TP53 c.919+1G>A Pathogenic ★★★ same condition
TP53 c.97-1G>A 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/tp53-p-arg175cys (accessed [today's date]).

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