Is TP53 p.Ser366Ala (c.1096T>G) pathogenic?

TP53 p.Ser366Ala (c.1096T>G) is classified Benign in TP53 (ClinVar, Expert panel, 15 submitters; last evaluated 2024-08-05). AlphaMissense: likely benign (0.0732); Ultra-rare (popmax 0.0184%, amr); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Ser366Ala (c.1096T>G)?

TP53 p.Ser366Ala (c.1096T>G) is associated with Li-Fraumeni syndrome, breast cancer, head and neck squamous cell carcinoma (ClinVar).

How common is TP53 p.Ser366Ala (c.1096T>G) in the general population?

TP53 p.Ser366Ala (c.1096T>G) is ultra-rare (popmax 0.0184%, amr) (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.Ser366Ala (c.1096T>G)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

TP53 p.Ser366Ala

c.1096T>G · rs17881470 · VCV135360

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, amr)

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 BS3 BP4

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.1096T>G variant in TP53 is a missense variant predicted to cause substitution of serine by alanine at amino acid 366 (p.Ser366Ala). This variant has been observed in at least 8 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, Internal lab contributors: SCV000214696.6). 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 = 0.1186; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 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). 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, BS3, BP4. (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024)

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

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.585	indeterminate
SaProt	LLR -7.46	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 3.3	GERP -1.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	17.95	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 0.0184% Admixed American · 11/59,898 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00787%

Overall 0.00676% 109/1,611,640 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0208%	4,802
Admixed Americangrpmax	0.0184%	5,445
European (non-Finnish)	0.00696%	14,367
African / African-American	0.004%	24,995

Remaining individuals 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.Ser366Ala
Coding: c.1096T>G
MANE Select: NM_000546
dbSNP: rs17881470
Type: single nucleotide variant
Location: chr17:7670613 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 366: a UniProt-annotated variant site (in a familial cancer not matching lfs; germline mutation and in sporadic cancers; somatic mutation); the 'interaction with carm1' region; the 'disordered' region; 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: breast cancer head and neck squamous cell carcinoma 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.Ser366Cys Uncertain significance ★★ ⚠ same residue
TP53 p.Ser366Pro Uncertain significance ★★ ⚠ same residue
TP53 p.Ser366Thr Uncertain significance ★★ ⚠ same residue
TP53 p.Ser366Phe Uncertain significance ★ ⚠ same residue
TP53 p.Ser366Tyr Uncertain significance ★ ⚠ 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-ser366ala (accessed [today's date]).

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