Is TP53 p.Arg158His (c.473G>A) pathogenic?

TP53 p.Arg158His (c.473G>A) is classified Pathogenic/Likely pathogenic in TP53 (ClinVar, Multiple submitters, 36 submitters; last evaluated 2026-07-22). AlphaMissense: likely pathogenic (0.9236); Very rare (popmax 0.00133%, afr); Associated with adrenocortical carcinoma, hereditary.

What condition is associated with TP53 p.Arg158His (c.473G>A)?

TP53 p.Arg158His (c.473G>A) is associated with adrenocortical carcinoma, hereditary, bone osteosarcoma, rhabdomyosarcoma (ClinVar).

How common is TP53 p.Arg158His (c.473G>A) in the general population?

TP53 p.Arg158His (c.473G>A) is very rare (popmax 0.00133%, afr) (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.Arg158His (c.473G>A)?

AlphaMissense predicts likely pathogenic (score 0.9236) — an in-silico prediction, not a clinical call.

TP53 p.Arg158His

c.473G>A · rs587782144 · VCV141963

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 36 submitters

AlphaMissense

likely pathogenic

0.9236 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adrenocortical carcinoma, hereditary

Computational evidence

Protein change
AlphaMissense	0.9236	likely pathogenic ✓ concordant with ClinVar
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -15.13	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 6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	22.9	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 0.00133% African / African-American · 1/74,914 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,614,006 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,914
South Asian	0.0011%	91,088
European (non-Finnish)	0.000424%	236,008

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.

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
		D	Dominant Negative
		D	Dominant Negative
Cancer	MDM2 Inhibitor AMGMDS3	D	Resistance

Variant & gene context

Gene: TP53
Protein: p.Arg158His
Coding: c.473G>A
MANE Select: NM_000546
dbSNP: rs587782144
Type: single nucleotide variant
Location: chr17:7675139 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 158: a DNA-binding region; the 'interaction with axin1' region; a β-strand; the 'interaction with ccar2' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation; requires 2 nucleotide substitutions); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic 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

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

Also linked: bone osteosarcoma rhabdomyosarcoma 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.Arg158Leu Pathogenic ★★★ same residue
TP53 p.Arg158Pro Pathogenic ★★★ same residue
TP53 p.Arg158Cys Uncertain significance ★★★ ⚠ same residue
TP53 p.Arg158Gly Pathogenic ★★ same residue
TP53 p.Arg158= Benign/Likely benign ★★ same residue
TP53 p.Arg158Ser Pathogenic ★ same residue
TP53 p.Arg158_Ala159del Pathogenic ★ same residue
TP53 p.Arg158_Tyr163del Likely pathogenic ★ same residue

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-arg158his (accessed [today's date]).

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