Is POLE p.Gln352Pro (c.1055A>C) pathogenic?

POLE p.Gln352Pro (c.1055A>C) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.6786); Very rare (popmax 0.00381%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Gln352Pro (c.1055A>C)?

POLE p.Gln352Pro (c.1055A>C) is associated with hereditary neoplastic syndrome, POLD1-related polyposis and colorectal cancer syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Gln352Pro (c.1055A>C) in the general population?

POLE p.Gln352Pro (c.1055A>C) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about POLE p.Gln352Pro (c.1055A>C)?

AlphaMissense predicts likely pathogenic (score 0.6786) — an in-silico prediction, not a clinical call.

POLE p.Gln352Pro

c.1055A>C · rs766094330 · VCV372024

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.6786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6786	likely pathogenic
REVEL	0.464	indeterminate
SaProt	LLR -11.93	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00381% European (non-Finnish) · 45/1,180,034 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00297% 48/1,614,118 alleles · very rare exomes 45/1,461,878 · genomes 3/152,240 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00381%	26,223
African / African-American	0.00267%	37,471
Admixed American	0.00167%	60,010

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.Gln352Pro
Coding: c.1055A>C
MANE Select: NM_006231
dbSNP: rs766094330
Type: single nucleotide variant
Location: chr12:132675786 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 352: an α-helix

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

Also linked: POLD1-related polyposis and colorectal cancer syndrome colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Gln352fs Conflicting classifications of pathogenicity ★ same residue
POLE p.Gln352Glu 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

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-gln352pro (accessed [today's date]).

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