Is TP53 p.Pro4Arg (c.11C>G) pathogenic?

TP53 p.Pro4Arg (c.11C>G) is classified Conflicting classifications of pathogenicity in TP53 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-04-25). AlphaMissense: likely benign (0.0932); Very rare (popmax 8.47e-05%, nfe); Associated with adrenocortical carcinoma, hereditary.

What condition is associated with TP53 p.Pro4Arg (c.11C>G)?

TP53 p.Pro4Arg (c.11C>G) is associated with adrenocortical carcinoma, hereditary, bone osteosarcoma, colorectal cancer (ClinVar).

How common is TP53 p.Pro4Arg (c.11C>G) in the general population?

TP53 p.Pro4Arg (c.11C>G) is very rare (popmax 8.47e-05%, nfe) (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.Pro4Arg (c.11C>G)?

AlphaMissense predicts likely benign (score 0.0932) — an in-silico prediction, not a clinical call.

TP53 p.Pro4Arg

c.11C>G · rs878854064 · VCV406582

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0932 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

adrenocortical carcinoma, hereditary

Computational evidence

Protein change
AlphaMissense	0.0932	likely benign
REVEL	0.533	indeterminate
SaProt	LLR -7.15	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 2.5	GERP -4.6, phastCons 0.37
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	15.76	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 8.47e-05% European (non-Finnish) · 1/1,179,978 alleles

Overall 6.84e-05% 1/1,461,780 alleles · very rare

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.Pro4Arg
Coding: c.11C>G
MANE Select: NM_000546
dbSNP: rs878854064
Type: single nucleotide variant
Location: chr17:7676584 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 4: an α-helix; the 'interaction with ccar2' region; the 'interaction with hrmt1l2' region; the 'transcription activation (acidic)' 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 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.Pro4Leu Likely benign ★★★ same residue
TP53 p.Pro4= Benign/Likely benign ★★ same residue
TP53 p.Pro4Ala Uncertain significance ★ ⚠ same residue
TP53 p.Pro4Ser Uncertain significance ★ ⚠ same residue
TP53 p.Pro4Gln 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-pro4arg (accessed [today's date]).

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