Is TP53 p.Arg333His (c.998G>A) pathogenic?

TP53 p.Arg333His (c.998G>A) is classified Benign in TP53 (ClinVar, Expert panel, 13 submitters; last evaluated 2025-03-04). AlphaMissense: likely benign (0.1281); Very rare (popmax 0.00879%, sas); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Arg333His (c.998G>A)?

TP53 p.Arg333His (c.998G>A) is associated with Li-Fraumeni syndrome, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is TP53 p.Arg333His (c.998G>A) in the general population?

TP53 p.Arg333His (c.998G>A) is very rare (popmax 0.00879%, 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.Arg333His (c.998G>A)?

AlphaMissense predicts likely benign (score 0.1281) — an in-silico prediction, not a clinical call.

TP53 p.Arg333His

c.998G>A · rs573154688 · VCV142273

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.1281 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00879%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

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

BS2_Moderate BS3 BP4_Moderate

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.998G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 333 (p.Arg333His). 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; ClinVar SCVs: SCV000285219.10). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0924; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3, BP4_Moderate. (Bayesian Points: -8; VCEP specifications version 2.3; 3/4/2025).

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

Computational evidence

Protein change
AlphaMissense	0.1281	likely benign
REVEL	0.554	indeterminate
SaProt	LLR -7.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 2, phastCons 0.54
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	19.36	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

Grpmax group 0.00879% South Asian · 8/91,026 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00316% 51/1,613,734 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00879%	11,378
African / African-American	0.004%	25,003
European (non-Finnish)	0.00331%	30,251
Remaining individualsnot grpmax-eligible	0.0016%	62,496

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.Arg333His
Coding: c.998G>A
MANE Select: NM_000546
dbSNP: rs573154688
Type: single nucleotide variant
Location: chr17:7670711 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 333: the 'interaction with carm1' region; a β-strand; the 'interaction with hipk2' region; the 'oligomerization' region; a modified residue (omega-n-methylarginine; 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

Also linked: 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.Arg333Cys Likely benign ★★★ ⚠ same residue
TP53 p.Arg333fs Pathogenic ★★ 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
TP53 p.Ala138Pro Likely pathogenic ★★★ same condition
TP53 p.Ala138Val Likely pathogenic ★★★ same condition
TP53 p.Ala347Asp 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-arg333his (accessed [today's date]).

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