Is TP53 p.Ala138= (c.414C>T) pathogenic?

TP53 p.Ala138= (c.414C>T) is classified Likely benign in TP53 (ClinVar, Expert panel, 4 submitters; last evaluated 2025-06-05). Very rare (popmax 8.47e-05%, nfe); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Ala138= (c.414C>T)?

TP53 p.Ala138= (c.414C>T) is associated with Li-Fraumeni syndrome, hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Ala138= (c.414C>T) in the general population?

TP53 p.Ala138= (c.414C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Li-Fraumeni syndrome inherited?

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

TP53 p.Ala138=

c.414C>T · rs1555526254 · VCV482234

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

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

PM2_Supporting BP7 BP4

Curation rationale (ClinGen, verbatim)

The c.414C>T (p.Ala138=) variant is a synonymous (silent) variant outside of the core splice motif, and BP4 code is met for splicing prediction (BP4, BP7). To our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met). This variant has an allele frequency of 6.195e-7 (1/1614158 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant (PS3/BS3 not met). The computational splicing predictor SpliceAI gives a score of [0.01], predicting that the variant has no impact on splicing (score threshold ≤ 0.10) (BP4). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BP4, BP7, PM2_Supporting. (Bayesian Points: -1; VCEP specifications version 2.3)

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

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 -1.6	GERP -4.6
Overall
CADD	3.553	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.2e-05% 1/1,614,158 alleles · very rare exomes 1/1,461,852 · genomes 0/152,306 · joint denominator

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.Ala138=
Coding: c.414C>T
MANE Select: NM_000546
dbSNP: rs1555526254
Type: single nucleotide variant
Location: chr17:7675198 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 138: a DNA-binding region; the 'interaction with axin1' region; the 'interaction with ccar2' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in lfs; germline mutation); the 'interaction with hipk1' region; 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.Ala138Pro Likely pathogenic ★★★ same residue
TP53 p.Ala138Val Likely pathogenic ★★★ same residue
TP53 p.Ala138Asp Uncertain significance ★★★ ⚠ same residue
TP53 p.Ala138Gly Uncertain significance ★★★ ⚠ same residue
TP53 p.Ala138Thr 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-ala138 (accessed [today's date]).

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