Is POLE p.Phe332= (c.996T>C) pathogenic?

POLE p.Phe332= (c.996T>C) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-21). Very rare (popmax 0.00552%, nfe); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Phe332= (c.996T>C)?

POLE p.Phe332= (c.996T>C) is associated with colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Phe332= (c.996T>C) in the general population?

POLE p.Phe332= (c.996T>C) is very rare (popmax 0.00552%, nfe) (gnomAD).

POLE p.Phe332=

c.996T>C · rs779159186 · VCV383015

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00552%, nfe)

Conditions

colorectal cancer, susceptibility to, 12

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 0.94	GERP -3.4, phastCons 0.99
Overall
CADD	3.051	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00552% European (non-Finnish) · 65/1,177,706 alleles

Filtering AF 0.00444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00404%

Overall 0.00429% 69/1,609,880 alleles · very rare exomes 66/1,457,640 · genomes 3/152,240 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00552%	18,119
Remaining individualsnot grpmax-eligible	0.00481%	20,778
African / African-American	0.00134%	74,700

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.Phe332=
Coding: c.996T>C
MANE Select: NM_006231
dbSNP: rs779159186
Type: single nucleotide variant
Location: chr12:132676118 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

Full POLE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

colorectal cancer, susceptibility to, 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

Similar variants

POLE p.Phe332Leu Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T 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
POLE c.1226+3A>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-phe332 (accessed [today's date]).

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