Is POLE p.Pro324= (c.972C>G) pathogenic?

POLE p.Pro324= (c.972C>G) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-11). Very rare (popmax 0.00401%, afr); Associated with Polymerase proofreading-related adenomatous polyposis.

What condition is associated with POLE p.Pro324= (c.972C>G)?

POLE p.Pro324= (c.972C>G) is associated with Polymerase proofreading-related adenomatous polyposis, colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Pro324= (c.972C>G) in the general population?

POLE p.Pro324= (c.972C>G) is very rare (popmax 0.00401%, afr) (gnomAD).

How is Polymerase proofreading-related polyposis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

POLE p.Pro324=

c.972C>G · rs745638752 · VCV413510

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

Polymerase proofreading-related adenomatous polyposis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.21	GERP -0.57, phastCons 0.86
Overall
CADD	9.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,844 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,612,816 alleles · very rare exomes 2/1,460,624 · genomes 2/152,192 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,948
European (non-Finnish)	8.48e-05%	1,179,568

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.Pro324=
Coding: c.972C>G
MANE Select: NM_006231
dbSNP: rs745638752
Type: single nucleotide variant
Location: chr12:132676142 (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

Polymerase proofreading-related adenomatous polyposis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer, susceptibility to, 12 hereditary neoplastic syndrome familial colorectal cancer type X

For Polymerase proofreading-related polyposis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

POLE p.Pro324Ala Uncertain significance ★★ ⚠ same residue
POLE p.Pro324Leu Uncertain significance ★★ ⚠ same residue
POLE p.Pro324Arg Uncertain significance ★ ⚠ same residue
POLE p.Pro324Thr 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

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-pro324 (accessed [today's date]).

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