Is POLE p.Pro441= (c.1323G>A) pathogenic?

POLE p.Pro441= (c.1323G>A) is classified Benign in POLE (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). Common (popmax 6.02%, eas) — too common for a highly-penetrant pathogenic allele; Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Pro441= (c.1323G>A)?

POLE p.Pro441= (c.1323G>A) is associated with colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome, Polymerase proofreading-related adenomatous polyposis (ClinVar).

POLE p.Pro441=

Q: How common is POLE p.Pro441= (c.1323G>A) in the general population?

POLE p.Pro441= (c.1323G>A) is common (popmax 6.02%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1323G>A · rs116573514 · VCV240387

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 6.02%, eas) — too common for a highly-penetrant pathogenic allele

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 -20	GERP -3.4
Overall
CADD	0.032	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.02% East Asian · 2,704/44,886 alleles

Filtering AF 5.83% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.76%

Overall 0.179% 2,888/1,613,658 alleles · common exomes 2,626/1,461,320 · genomes 262/152,338 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	6.02%	17
Remaining individualsnot grpmax-eligible	0.11%	906
South Asian	0.0615%	1,627
Middle Eastern	0.033%	3,029
Admixed American	0.00833%	12,005
African / African-American	0.004%	25,021
European (non-Finnish)	0.0039%	25,652
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Finnishnot grpmax-eligible	0.00315%	31,761

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.Pro441=
Coding: c.1323G>A
MANE Select: NM_006231
dbSNP: rs116573514
Type: single nucleotide variant
Location: chr12:132673611 (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 Polymerase proofreading-related adenomatous polyposis

Similar variants

POLE p.Pro441Ala Uncertain significance ★★ ⚠ same residue
POLE p.Pro441Arg Uncertain significance ★★ ⚠ same residue
POLE p.Pro441Leu Uncertain significance ★★ ⚠ same residue
POLE p.Pro441Ser 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-pro441 (accessed [today's date]).

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