Is POLE p.Met295Val (c.883A>G) pathogenic?

POLE p.Met295Val (c.883A>G) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-30). AlphaMissense: likely pathogenic (0.943); Absent from gnomAD v4.1; Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Met295Val (c.883A>G)?

POLE p.Met295Val (c.883A>G) is associated with colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Met295Val (c.883A>G) in the general population?

POLE p.Met295Val (c.883A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLE p.Met295Val (c.883A>G)?

AlphaMissense predicts likely pathogenic (score 0.943) — an in-silico prediction, not a clinical call.

POLE p.Met295Val

c.883A>G · rs2136015636 · VCV2677938

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.943 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

colorectal cancer, susceptibility to, 12

Computational evidence

Protein change
AlphaMissense	0.943	likely pathogenic
REVEL	0.647	pathogenic-leaning
SaProt	LLR -14.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POLE
Protein: p.Met295Val
Coding: c.883A>G
MANE Select: NM_006231
dbSNP: rs2136015636
Type: single nucleotide variant
Location: chr12:132676572 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 295: 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.Met295Arg Uncertain significance ★ ⚠ same residue
POLE p.Met295Leu 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-met295val (accessed [today's date]).

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