Is POLE p.Ser1525Arg (c.4575C>G) pathogenic?

POLE p.Ser1525Arg (c.4575C>G) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-12). AlphaMissense: likely pathogenic (0.7298); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ser1525Arg (c.4575C>G)?

POLE p.Ser1525Arg (c.4575C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ser1525Arg (c.4575C>G) in the general population?

POLE p.Ser1525Arg (c.4575C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLE p.Ser1525Arg (c.4575C>G)?

AlphaMissense predicts likely pathogenic (score 0.7298) — an in-silico prediction, not a clinical call.

POLE p.Ser1525Arg

c.4575C>G · rs2138542931 · VCV2447945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7298 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7298	likely pathogenic
REVEL	0.052	moderately benign-leaning
SaProt	LLR -7.43	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 2.9	GERP -0.54, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	16.07	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.Ser1525Arg
Coding: c.4575C>G
MANE Select: NM_006231
dbSNP: rs2138542931
Type: single nucleotide variant
Location: chr12:132642973 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1525: an α-helix; a UniProt-annotated variant site (in imagei)

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLE p.Ser1525Ile Uncertain significance ★★ ⚠ same residue
POLE p.Ser1525= Likely benign ★★ same residue
POLE p.Ser1525Asn Uncertain significance ★ ⚠ same residue
POLE p.Ser1525Thr Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.1020+5G>A Uncertain significance ★★ same condition
POLE c.1106+3G>C 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-ser1525arg (accessed [today's date]).

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