Is TP53 p.Arg181Ser (c.541C>A) pathogenic?

TP53 p.Arg181Ser (c.541C>A) is classified Uncertain significance in TP53 (ClinVar, Expert panel, 4 submitters; last evaluated 2025-03-04). AlphaMissense: likely pathogenic (0.9524); Absent from gnomAD v4.1; Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Arg181Ser (c.541C>A)?

TP53 p.Arg181Ser (c.541C>A) is associated with Li-Fraumeni syndrome, hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Arg181Ser (c.541C>A) in the general population?

TP53 p.Arg181Ser (c.541C>A) is absent from gnomAD v4.1 (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.Arg181Ser (c.541C>A)?

AlphaMissense predicts likely pathogenic (score 0.9524) — an in-silico prediction, not a clinical call.

TP53 p.Arg181Ser

c.541C>A · rs587782596 · VCV230764

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9524 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

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

PP3_Moderate PM2_Supporting BS2_Supporting BS3_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000546.6:c.541C>A variant in TP53 is a missense variant predicted to cause substitution of arginine by serine at amino acid 181 (p.Arg181Ser). This variant has been observed in 3 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_Supporting; Ambry SCV000274425.4). This variant received a total of 0.5 points across 1 family meeting Chompret criteria and does not meet criteria for PS4 (PS4 not met; IARC database). This variant is absent from gnomAD v4.1.0 (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). Computational predictor scores (BayesDel = 0.204; Align GVGD = Class C65) 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). In summary, this variant meets the criteria to be classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, PM2_supporting, BS3_supporting, PP3_moderate (Bayesian Points: 1; VCEP specifications version 2.3).

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

Computational evidence

Protein change
AlphaMissense	0.9524	likely pathogenic
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	23.9	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: TP53
Protein: p.Arg181Ser
Coding: c.541C>A
MANE Select: NM_000546
dbSNP: rs587782596
Type: single nucleotide variant
Location: chr17:7675071 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 181: a DNA-binding region; the 'interaction with axin1' region; a β-strand; the 'interaction with ccar2' region; a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a familial cancer not matching lfs; germline mutation and 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

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

Also linked: hereditary neoplastic syndrome

For Li-Fraumeni syndrome (Orphanet):

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

Similar variants

TP53 p.Arg181Cys Likely pathogenic ★★★ ⚠ same residue
TP53 p.Arg181His Pathogenic/Likely pathogenic ★★ ⚠ same residue
TP53 p.Arg181Pro Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Arg181= Benign/Likely benign ★★ same residue
TP53 p.Arg181Leu 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-arg181ser (accessed [today's date]).

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