Is POLE p.Ile344Phe (c.1030A>T) pathogenic?

POLE p.Ile344Phe (c.1030A>T) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.6938); Absent from gnomAD v4.1.

How common is POLE p.Ile344Phe (c.1030A>T) in the general population?

POLE p.Ile344Phe (c.1030A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLE p.Ile344Phe (c.1030A>T)?

AlphaMissense predicts likely pathogenic (score 0.6938) — an in-silico prediction, not a clinical call.

POLE p.Ile344Phe

c.1030A>T · rs2136011987 · VCV1353419

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6938 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6938	likely pathogenic
REVEL	0.284	benign-leaning
SaProt	LLR -10.98	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.34	acceptor gain · deltas
Pangolin	Δ0.20	gain · loss 0.09 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.97	GERP -0.62, phastCons 0.81
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

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.Ile344Phe
Coding: c.1030A>T
MANE Select: NM_006231
dbSNP: rs2136011987
Type: single nucleotide variant
Location: chr12:132675811 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 344: an α-helix

Full POLE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

POLE p.Ile344= Benign/Likely benign ★★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same type
POLE c.3276-1G>C Likely pathogenic ★★ same type
POLE c.5678+1G>T Pathogenic ★★ same type
POLE p.Gln1763Ter Pathogenic/Likely pathogenic ★★ same type
POLE p.Leu424Val Pathogenic ★★ same type
POLE p.Pro436Ser Likely pathogenic ★★ ⚠ same type
POLE c.1020+5G>A Uncertain significance ★★ same type

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-ile344phe (accessed [today's date]).

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