Is TP53 p.His168= (c.504C>T) pathogenic?

TP53 p.His168= (c.504C>T) is classified Benign/Likely benign in TP53 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-17). Ultra-rare (popmax 0.0329%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with TP53 p.His168= (c.504C>T)?

TP53 p.His168= (c.504C>T) is associated with hereditary neoplastic syndrome, Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.His168= (c.504C>T) in the general population?

TP53 p.His168= (c.504C>T) is ultra-rare (popmax 0.0329%, sas) (gnomAD).

TP53 p.His168=

c.504C>T · rs746293837 · VCV220778

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -3.5, phastCons 1
Overall
CADD	4.685	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% South Asian · 30/91,090 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00186% 30/1,614,228 alleles · ultra-rare exomes 30/1,461,882 · genomes 0/152,346 · joint denominator

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.His168=
Coding: c.504C>T
MANE Select: NM_000546
dbSNP: rs746293837
Type: single nucleotide variant
Location: chr17:7675108 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 168: a DNA-binding region; the 'interaction with axin1' region; an α-helix; the 'interaction with ccar2' region; a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); 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); 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

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

Also linked: Li-Fraumeni syndrome

Similar variants

TP53 p.His168Leu Pathogenic ★ same residue
TP53 p.His168Pro Likely pathogenic ★ same residue
TP53 p.His168Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.His168Gln Uncertain significance ★ ⚠ same residue
TP53 p.His168Tyr Uncertain significance ★ ⚠ same residue
TP53 p.His168_Ser185delinsArg Uncertain significance ★ same residue
TP53 p.His168Asn Uncertain significance 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-his168 (accessed [today's date]).

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