Is TP53 p.Arg156His (c.467G>A) pathogenic?

TP53 p.Arg156His (c.467G>A) is classified Uncertain significance in TP53 (ClinVar, Expert panel, 24 submitters; last evaluated 2021-02-22). AlphaMissense: likely benign (0.1586); Very rare (popmax 0.00668%, eas); Associated with Li-Fraumeni syndrome 1.

What condition is associated with TP53 p.Arg156His (c.467G>A)?

TP53 p.Arg156His (c.467G>A) is associated with Li-Fraumeni syndrome 1, bone osteosarcoma, hereditary breast ovarian cancer syndrome (ClinVar).

How common is TP53 p.Arg156His (c.467G>A) in the general population?

TP53 p.Arg156His (c.467G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about TP53 p.Arg156His (c.467G>A)?

AlphaMissense predicts likely benign (score 0.1586) — an in-silico prediction, not a clinical call.

TP53 p.Arg156His

c.467G>A · rs371524413 · VCV127811

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 24 submitters

AlphaMissense

likely benign

0.1586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Li-Fraumeni syndrome 1

ClinGen expert panel — TP53 VCEP

Uncertain Significance for Li-Fraumeni syndrome 1. Applied ACMG criteria (verbatim):

PS4_Moderate BS2_Supporting BS3_Supporting

Curation rationale (ClinGen, verbatim)

This variant has been reported in 4 probands meeting Revised Chompret criteria (PS4_Supporting; Internal laboratory and clinical contributors, SCV000186315.7). This variant has been observed in 4 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor, SCV000186315.7). Transactivation assays show a partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.467G>A (p.Arg156His) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_moderate; BS2_supporting; BS4_supporting.

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

Computational evidence

Protein change
AlphaMissense	0.1586	likely benign
REVEL	0.627	indeterminate
SaProt	LLR -9.74	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 1.4	GERP -0.88, phastCons 0.76
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	17.59	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00668% East Asian · 3/44,892 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00341% 55/1,614,024 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,964
European (non-Finnish)	0.00398%	25,107
South Asian	0.0022%	45,544
Admixed American	0.00167%	59,992
Finnishnot grpmax-eligible	0.00156%	64,020
African / African-American	0.00134%	74,906

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.Arg156His
Coding: c.467G>A
MANE Select: NM_000546
dbSNP: rs371524413
Type: single nucleotide variant
Location: chr17:7675145 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 156: 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 lfs; germline mutation and in sporadic cancers; 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

Li-Fraumeni syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: bone osteosarcoma hereditary breast ovarian cancer syndrome colorectal cancer hepatocellular carcinoma adrenocortical carcinoma, hereditary choroid plexus papilloma head and neck squamous cell carcinoma 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

Similar variants

TP53 p.Arg156Pro Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Arg156= Benign/Likely benign ★★ same residue
TP53 p.Arg156Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Arg156Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Arg156Ser Uncertain significance ★ ⚠ same residue
TP53 p.Arg156_Arg158del Pathogenic ★ same residue
TP53 c.375+5G>A Likely pathogenic ★★★ same condition
TP53 c.919+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-arg156his (accessed [today's date]).

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