Is POLE p.Ala341Pro (c.1021G>C) pathogenic?

POLE p.Ala341Pro (c.1021G>C) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.1384); Very rare (popmax 0.000424%, nfe); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Ala341Pro (c.1021G>C)?

POLE p.Ala341Pro (c.1021G>C) is associated with colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala341Pro (c.1021G>C) in the general population?

POLE p.Ala341Pro (c.1021G>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about POLE p.Ala341Pro (c.1021G>C)?

AlphaMissense predicts likely benign (score 0.1384) — an in-silico prediction, not a clinical call.

POLE p.Ala341Pro

c.1021G>C · rs137860861 · VCV405664

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1384 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

colorectal cancer, susceptibility to, 12

Computational evidence

Protein change
AlphaMissense	0.1384	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.47 · evaluated, not missing
Pangolin	Δ0.37	loss · gain 0.05 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 3.3	GERP 0.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000424% European (non-Finnish) · 5/1,178,698 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,612,720 alleles · very rare exomes 5/1,460,418 · genomes 0/152,302 · joint denominator

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.Ala341Pro
Coding: c.1021G>C
MANE Select: NM_006231
dbSNP: rs137860861
Type: single nucleotide variant
Location: chr12:132675820 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 341: an α-helix

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.Ala341= Likely benign ★★ same residue
POLE p.Ala341Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ala341Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ala341Val Likely benign ★ same residue
POLE p.Ala341Thr 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

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-ala341pro (accessed [today's date]).

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