Is POLE p.Lys398= (c.1194G>A) pathogenic?

POLE p.Lys398= (c.1194G>A) is classified Likely benign in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-19). Absent from gnomAD v4.1; Associated with POLD1-related polyposis and colorectal cancer syndrome.

What condition is associated with POLE p.Lys398= (c.1194G>A)?

POLE p.Lys398= (c.1194G>A) is associated with POLD1-related polyposis and colorectal cancer syndrome (ClinVar).

How common is POLE p.Lys398= (c.1194G>A) in the general population?

POLE p.Lys398= (c.1194G>A) is absent from gnomAD v4.1 (gnomAD).

How is Polymerase proofreading-related polyposis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

POLE p.Lys398=

c.1194G>A · rs1593076741 · VCV766373

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

POLD1-related polyposis and colorectal cancer syndrome

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 1.1	GERP -0.49, phastCons 1
Overall
CADD	8.835	PHRED · no single calibrated threshold — expert panels disagree

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.Lys398=
Coding: c.1194G>A
MANE Select: NM_006231
dbSNP: rs1593076741
Type: single nucleotide variant
Location: chr12:132675430 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

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

Disease context

POLD1-related polyposis and colorectal cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Polymerase proofreading-related polyposis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

POLE p.Lys398Arg Uncertain significance ★★ ⚠ same residue
POLE p.Lys398Gln Uncertain significance ★ ⚠ same residue
POLE p.Lys398Glu Uncertain significance ★ ⚠ same residue
POLE p.Arg1390Cys Uncertain significance ★★ ⚠ same condition
POLE p.Arg1471His Uncertain significance ★★ ⚠ same condition
POLE p.Gln352Pro Uncertain significance ★★ ⚠ same condition
POLE p.Glu2141Lys Uncertain significance ★★ ⚠ same condition
POLE p.Leu938Phe 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-lys398 (accessed [today's date]).

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