Is POLE p.Ala781= (c.2343G>A) pathogenic?

POLE p.Ala781= (c.2343G>A) is classified Likely benign in POLE (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0495%, mid); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Ala781= (c.2343G>A)?

POLE p.Ala781= (c.2343G>A) is associated with colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala781= (c.2343G>A) in the general population?

POLE p.Ala781= (c.2343G>A) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

POLE p.Ala781=

c.2343G>A · rs199751241 · VCV484470

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

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 -9.3	GERP -3.7
Overall
CADD	0.123	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,060 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00167% 27/1,611,968 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,020
East Asian	0.0134%	7,481
Admixed American	0.00667%	15,003
Finnishnot grpmax-eligible	0.00161%	62,098
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00133%	75,026
European (non-Finnish)	0.000932%	107,255

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.Ala781=
Coding: c.2343G>A
MANE Select: NM_006231
dbSNP: rs199751241
Type: single nucleotide variant
Location: chr12:132665427 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 781: an α-helix; a UniProt-annotated variant site (in imagei)

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.Ala781Pro Uncertain significance ★★ ⚠ same residue
POLE p.Ala781Ser Uncertain significance ★★ ⚠ same residue
POLE p.Ala781Val Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ala781Glu Uncertain significance ★ ⚠ same residue
POLE p.Ala781Gly Uncertain significance ★ ⚠ same residue
POLE p.Ala781Thr Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T Pathogenic ★★ 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-ala781 (accessed [today's date]).

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