Is TP53 p.Ala138Asp (c.413C>A) pathogenic?

TP53 p.Ala138Asp (c.413C>A) is classified Uncertain significance in TP53 (ClinVar, Expert panel, 3 submitters; last evaluated 2025-06-05). AlphaMissense: likely pathogenic (0.9364); Absent from gnomAD v4.1; Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Ala138Asp (c.413C>A)?

TP53 p.Ala138Asp (c.413C>A) is associated with Li-Fraumeni syndrome, hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Ala138Asp (c.413C>A) in the general population?

TP53 p.Ala138Asp (c.413C>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.Ala138Asp (c.413C>A)?

AlphaMissense predicts likely pathogenic (score 0.9364) — an in-silico prediction, not a clinical call.

TP53 p.Ala138Asp

c.413C>A · rs750600586 · VCV528270

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9364 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

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

PP3_Moderate PM2_Supporting PM5_Supporting BS3_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.413C>A variant in TP53 is a missense variant predicted to cause substitution of alanine by asparginine at amino acid 138 (p.Ala138Asp). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant received a total of 0.5 points across one proband. (PS4 not met; Internal lab contributor). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.5405; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). Another missense variant (c.412G>C (p.Ala138Pro)) (ClinVar Variation ID: 12376), in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_supporting, BS3_supporting, PP3_moderate, PM5_Supporting. (Bayesian Points: 3; VCEP specifications version 2.3)

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

Computational evidence

Protein change
AlphaMissense	0.9364	likely pathogenic
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -11.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Ala138Asp
Coding: c.413C>A
MANE Select: NM_000546
dbSNP: rs750600586
Type: single nucleotide variant
Location: chr17:7675199 (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.Ala138Gly Uncertain significance ★★★ ⚠ same residue
TP53 p.Ala138Thr Uncertain significance ★★★ ⚠ same residue
TP53 p.Ala138= 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-ala138asp (accessed [today's date]).

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