Is POLE p.Asp368Asn (c.1102G>A) pathogenic?

POLE p.Asp368Asn (c.1102G>A) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-03-05). AlphaMissense: likely pathogenic (0.9919); Absent from gnomAD v4.1; Associated with Polymerase proofreading-related adenomatous polyposis.

What condition is associated with POLE p.Asp368Asn (c.1102G>A)?

POLE p.Asp368Asn (c.1102G>A) is associated with Polymerase proofreading-related adenomatous polyposis, colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Asp368Asn (c.1102G>A) in the general population?

POLE p.Asp368Asn (c.1102G>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.

What do computational predictors say about POLE p.Asp368Asn (c.1102G>A)?

AlphaMissense predicts likely pathogenic (score 0.9919) — an in-silico prediction, not a clinical call.

POLE p.Asp368Asn

c.1102G>A · rs1593077422 · VCV822177

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9919 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Polymerase proofreading-related adenomatous polyposis

Computational evidence

Protein change
AlphaMissense	0.9919	likely pathogenic · top 8% in POLE
REVEL	0.529	indeterminate
SaProt	LLR -12.58	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	32.0	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.Asp368Asn
Coding: c.1102G>A
MANE Select: NM_006231
dbSNP: rs1593077422
Type: single nucleotide variant
Location: chr12:132675739 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 368: an α-helix

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

Disease context

Polymerase proofreading-related adenomatous polyposis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer, susceptibility to, 12 hereditary neoplastic syndrome

For Polymerase proofreading-related polyposis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

POLE p.Asp368Gly Uncertain significance ★★ ⚠ same residue
POLE p.Asp368= Benign/Likely benign ★★ same residue
POLE p.Asp368Glu Uncertain significance ★ ⚠ same residue
POLE p.Asp368Val Uncertain significance ★ ⚠ same residue
POLE p.Asp368Ter Uncertain significance ★ same residue
POLE p.Asp368Tyr Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T 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-asp368asn (accessed [today's date]).

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