Is POLE p.Asp262Glu (c.786C>A) pathogenic?

POLE p.Asp262Glu (c.786C>A) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-23). AlphaMissense: likely pathogenic (0.577); Absent from gnomAD v4.1.

How common is POLE p.Asp262Glu (c.786C>A) in the general population?

POLE p.Asp262Glu (c.786C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLE p.Asp262Glu (c.786C>A)?

AlphaMissense predicts likely pathogenic (score 0.577) — an in-silico prediction, not a clinical call.

POLE p.Asp262Glu

c.786C>A · rs201223598 · VCV1005380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.577 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.577	likely pathogenic
REVEL	0.198	benign-leaning
SaProt	LLR -8.84	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	22.8	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.Asp262Glu
Coding: c.786C>A
MANE Select: NM_006231
dbSNP: rs201223598
Type: single nucleotide variant
Location: chr12:132677378 (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

Similar variants

POLE p.Asp262His Uncertain significance ★★ ⚠ same residue
POLE p.Asp262= Likely benign ★★ same residue
POLE p.Asp262Ala Uncertain significance ★ ⚠ 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

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-asp262glu (accessed [today's date]).

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