Is POLE p.Ile307= (c.921C>T) pathogenic?

POLE p.Ile307= (c.921C>T) is classified Benign in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-07). Very rare (popmax 0.0011%, sas); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Ile307= (c.921C>T)?

POLE p.Ile307= (c.921C>T) is associated with colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Ile307= (c.921C>T) in the general population?

POLE p.Ile307= (c.921C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

POLE p.Ile307=

c.921C>T · VCV3904207

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

colorectal cancer, susceptibility to, 12

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.20	acceptor loss, 48 bp away · masked 0 · deltas
Pangolin	Δ0.26	loss · gain 0.24 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	16.49	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,950 alleles

Overall 6.85e-05% 1/1,459,966 alleles · very rare

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.Ile307=
Coding: c.921C>T
MANE Select: NM_006231
Type: single nucleotide variant
Location: chr12:132676193 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 307: a β-strand

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

Similar variants

POLE p.Ile307Leu Uncertain significance ★ ⚠ same residue
POLE p.Ile307Val Uncertain significance ★ ⚠ same residue
POLE c.5678+1G>T Pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.5378+4C>T Uncertain significance ★★ same condition
POLE p.Ala107Val Uncertain significance ★★ ⚠ same condition
POLE p.Ala1149Val Uncertain significance ★★ ⚠ same condition
POLE p.Ala1323Val 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-ile307 (accessed [today's date]).

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