Is POLE p.Tyr152= (c.456C>T) pathogenic?

POLE p.Tyr152= (c.456C>T) is classified Likely benign in POLE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-29). Ultra-rare (popmax 0.011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Tyr152= (c.456C>T)?

POLE p.Tyr152= (c.456C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Tyr152= (c.456C>T) in the general population?

POLE p.Tyr152= (c.456C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

POLE p.Tyr152=

c.456C>T · rs560617100 · VCV682224

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.2	GERP -2.7, phastCons 1
Overall
CADD	1.619	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% South Asian · 10/91,058 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.000682% 11/1,612,862 alleles · ultra-rare exomes 9/1,460,532 · genomes 2/152,330 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,106
Remaining individualsnot grpmax-eligible	0.0016%	62,466

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: POLE
Protein: p.Tyr152=
Coding: c.456C>T
MANE Select: NM_006231
dbSNP: rs560617100
Type: single nucleotide variant
Location: chr12:132679619 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 152: a β-strand

Full POLE 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

Similar variants

POLE p.Tyr152Asp Uncertain significance ★ ⚠ same residue
POLE p.Tyr152Cys Uncertain significance ★ ⚠ same residue
POLE p.Tyr152His Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.1020+5G>A Uncertain significance ★★ same condition
POLE c.1106+3G>C Uncertain significance ★★ same condition
POLE c.1106+4A>G Uncertain significance ★★ 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/pole-p-tyr152 (accessed [today's date]).

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