Is TP53 p.Arg335= (c.1005T>G) pathogenic?

TP53 p.Arg335= (c.1005T>G) is classified Likely benign in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-27). Very rare (popmax 0.00331%, nfe); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Arg335= (c.1005T>G)?

TP53 p.Arg335= (c.1005T>G) is associated with Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Arg335= (c.1005T>G) in the general population?

TP53 p.Arg335= (c.1005T>G) is very rare (popmax 0.00331%, nfe) (gnomAD).

How is Li-Fraumeni syndrome inherited?

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

TP53 p.Arg335=

c.1005T>G · rs2150995287 · VCV1086350

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP -4
Overall
CADD	5.608	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00331% European (non-Finnish) · 39/1,179,318 alleles

Filtering AF 0.00248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00267% 43/1,613,274 alleles · very rare exomes 43/1,461,012 · genomes 0/152,262 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
European (non-Finnish)grpmax	0.00331%	30,239
African / African-American	0.00267%	37,513
Remaining individualsnot grpmax-eligible	0.0016%	62,468

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg335=
Coding: c.1005T>G
MANE Select: NM_000546
dbSNP: rs2150995287
Type: single nucleotide variant
Location: chr17:7670704 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 335: a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); the 'interaction with carm1' region; an α-helix; the 'interaction with hipk2' region; the 'oligomerization' region; a modified residue (symmetric dimethylarginine; by prmt5); the 'interaction with hipk1' 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

For Li-Fraumeni syndrome (Orphanet):

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

Similar variants

TP53 p.Arg335Cys Likely benign ★★★ same residue
TP53 p.Arg335His Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Arg335Pro Uncertain significance ★ ⚠ same residue
TP53 p.Arg335_Glu336insGlyArg Likely pathogenic ★ same residue
TP53 p.Arg335Leu Likely benign ★ 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-arg335 (accessed [today's date]).

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