Is TP53 p.Arg110Pro (c.329G>C) pathogenic?

TP53 p.Arg110Pro (c.329G>C) is classified Pathogenic in TP53 (ClinVar, Expert panel, 9 submitters; last evaluated 2025-06-05). AlphaMissense: likely pathogenic (0.9045); Absent from gnomAD v4.1; Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Arg110Pro (c.329G>C)?

TP53 p.Arg110Pro (c.329G>C) is associated with Li-Fraumeni syndrome, adrenocortical carcinoma, hereditary, hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Arg110Pro (c.329G>C) in the general population?

TP53 p.Arg110Pro (c.329G>C) 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.Arg110Pro (c.329G>C)?

AlphaMissense predicts likely pathogenic (score 0.9045) — an in-silico prediction, not a clinical call.

TP53 p.Arg110Pro

c.329G>C · rs11540654 · VCV233627

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9045 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

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

PM2_Supporting PS4_Supporting PS2_Moderate PS3 PM1

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.329G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 110 (p.Arg110Pro). This variant has been reported in 2 unrelated families meeting Revised Chompret criteria and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs: 30455982, 23894400; Internal lab contributors). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a moderately LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID: 29070607). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 11 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PM1, PS2_Moderate, PM2_Supporting, PS4_Supporting. (Bayesian Points: 10; VCEP specifications version 2.3)

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

Computational evidence

Protein change
AlphaMissense	0.9045	likely pathogenic ✓ concordant with ClinVar
REVEL	0.593	indeterminate
SaProt	LLR -17.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.1	GERP -4.4
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	17.49	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.Arg110Pro
Coding: c.329G>C
MANE Select: NM_000546
dbSNP: rs11540654
Type: single nucleotide variant
Location: chr17:7676040 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 110: a DNA-binding region; a β-strand; the 'interaction with ccar2' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in a familial cancer not matching lfs; germline mutation and in sporadic cancers; somatic mutation; does not induce snai1 degradation); the 'interaction with wwox' region; the 'interaction with hipk1' region; the 'required for interaction with znf385a' 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: adrenocortical carcinoma, hereditary hereditary neoplastic syndrome hereditary breast carcinoma

For Li-Fraumeni syndrome (Orphanet):

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

Similar variants

TP53 p.Arg110Gly Likely pathogenic ★★★ ⚠ same residue
TP53 p.Arg110Leu Pathogenic ★★★ ⚠ same residue
TP53 p.Arg110Cys Uncertain significance ★★★ ⚠ same residue
TP53 p.Arg110His Likely benign ★★★ same residue
TP53 p.Arg110Ser Uncertain significance ★★ ⚠ same residue
TP53 p.Arg110= Benign/Likely benign ★★ same residue
TP53 p.Arg110_Phe113del Likely pathogenic ★★ same residue
TP53 p.Arg110fs Pathogenic ★★ 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-arg110pro (accessed [today's date]).

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