Is TP53 p.Phe212Ile (c.634T>A) pathogenic?

TP53 p.Phe212Ile (c.634T>A) is classified Uncertain significance in TP53 (ClinVar, Expert panel, 6 submitters; last evaluated 2026-02-05). AlphaMissense: likely pathogenic (0.5688); Absent from gnomAD v4.1; Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Phe212Ile (c.634T>A)?

TP53 p.Phe212Ile (c.634T>A) is associated with Li-Fraumeni syndrome, hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Phe212Ile (c.634T>A) in the general population?

TP53 p.Phe212Ile (c.634T>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.Phe212Ile (c.634T>A)?

AlphaMissense predicts likely pathogenic (score 0.5688) — an in-silico prediction, not a clinical call.

TP53 p.Phe212Ile

c.634T>A · rs1064795766 · VCV422414

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.5688 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

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

PM2_Supporting PS4_Supporting BP4

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.634T>A variant in TP53 is a missense variant predicted to cause substitution of phenylalanine by isoleucine at amino acid 212 (p.Phe212Ile). This variant has been reported in 2 unrelated proband smeeting 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; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 16007150, 29979965, 30224644). Computational predictor scores (BayesDel = -0.00674022; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -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). In summary, this variant meets the criteria to be classified as of uncertain significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, BP4, PM2_supporting. (Bayesian Points: 1; VCEP specifications version 2.4)

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

Computational evidence

Protein change
AlphaMissense	0.5688	likely pathogenic
REVEL	0.478	indeterminate
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -0.51, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	19.14	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.Phe212Ile
Coding: c.634T>A
MANE Select: NM_000546
dbSNP: rs1064795766
Type: single nucleotide variant
Location: chr17:7674897 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 212: a DNA-binding region; the 'interaction with axin1' region; the 'interaction with ccar2' region; the 'interaction with hipk1' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); 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.Phe212Ser 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
TP53 p.Ala138Pro Likely pathogenic ★★★ same condition
TP53 p.Ala138Val Likely pathogenic ★★★ same condition
TP53 p.Ala347Asp Pathogenic ★★★ same condition
TP53 p.Arg110Gly Likely 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-phe212ile (accessed [today's date]).

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