Is TP53 p.Pro278Ala (c.832C>G) pathogenic?

TP53 p.Pro278Ala (c.832C>G) is classified Conflicting classifications of pathogenicity in TP53 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-05-26). AlphaMissense: likely pathogenic (0.9934); Absent from gnomAD v4.1; Associated with adrenocortical carcinoma, hereditary.

What condition is associated with TP53 p.Pro278Ala (c.832C>G)?

TP53 p.Pro278Ala (c.832C>G) is associated with adrenocortical carcinoma, hereditary, bone osteosarcoma, colorectal cancer (ClinVar).

How common is TP53 p.Pro278Ala (c.832C>G) in the general population?

TP53 p.Pro278Ala (c.832C>G) is absent from gnomAD v4.1 (gnomAD).

How is Adrenocortical carcinoma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TP53 p.Pro278Ala (c.832C>G)?

AlphaMissense predicts likely pathogenic (score 0.9934) — an in-silico prediction, not a clinical call.

TP53 p.Pro278Ala

c.832C>G · rs17849781 · VCV376645

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9934 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adrenocortical carcinoma, hereditary

Computational evidence

Protein change
AlphaMissense	0.9934	likely pathogenic · top 8% in TP53
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -12.50	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	26.2	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.Pro278Ala
Coding: c.832C>G
MANE Select: NM_000546
dbSNP: rs17849781
Type: single nucleotide variant
Location: chr17:7673788 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 278: a DNA-binding region; the 'interaction with axin1' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation; requires 2 nucleotide substitutions); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation); the 'interaction with e4f1' region; the 'interaction with dna' region; an α-helix; the 'interaction with ccar2' region; the 'interaction with hipk1' region; the 'required for interaction with znf385a' region

Full TP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

adrenocortical carcinoma, hereditary — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: bone osteosarcoma colorectal cancer hepatocellular carcinoma choroid plexus papilloma basal cell carcinoma, susceptibility to, 7 familial pancreatic carcinoma hereditary neoplastic syndrome nasopharyngeal carcinoma hereditary breast carcinoma Li-Fraumeni syndrome ovarian neoplasm glioma susceptibility 1 bone marrow failure syndrome 5

For Adrenocortical carcinoma (Orphanet):

Inheritance: Not applicable
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

TP53 p.Pro278His Pathogenic ★★★ same residue
TP53 p.Pro278Leu Pathogenic ★★ same residue
TP53 p.Pro278Ser Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Pro278Thr Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Pro278Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Pro278_Arg283dup Uncertain significance ★★ same residue
TP53 p.Pro278fs Pathogenic ★ same residue
TP53 c.375+5G>A 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-pro278ala (accessed [today's date]).

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