Is POLE p.Arg1382Ser (c.4144C>A) pathogenic?

POLE p.Arg1382Ser (c.4144C>A) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: ambiguous (0.5348); Absent from gnomAD v4.1.

How common is POLE p.Arg1382Ser (c.4144C>A) in the general population?

POLE p.Arg1382Ser (c.4144C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLE p.Arg1382Ser (c.4144C>A)?

AlphaMissense predicts ambiguous (score 0.5348) — an in-silico prediction, not a clinical call.

POLE p.Arg1382Ser

c.4144C>A · rs5744904 · VCV2113163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5348 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5348	ambiguous
REVEL	0.195	benign-leaning
SaProt	LLR -8.95	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	23.2	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.Arg1382Ser
Coding: c.4144C>A
MANE Select: NM_006231
dbSNP: rs5744904
Type: single nucleotide variant
Location: chr12:132648934 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1382: a UniProt-annotated variant site (in imagei); a UniProt-annotated variant site (found in a colorectal sample; somatic mutation)

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

Similar variants

POLE p.Arg1382Cys Uncertain significance ★★ ⚠ same residue
POLE p.Arg1382Leu Uncertain significance ★★ ⚠ same residue
POLE p.Arg1382= Likely benign ★★ same residue
POLE p.Arg1382Gly Uncertain significance ★ ⚠ same residue
POLE p.Arg1382His Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg1382fs Pathogenic ★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same type
POLE c.3276-1G>C Likely 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-arg1382ser (accessed [today's date]).

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