Is POLE p.Arg924Ser (c.2770C>A) pathogenic?

POLE p.Arg924Ser (c.2770C>A) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-10-12). AlphaMissense: ambiguous (0.5615); No allele count reported in gnomAD v4.1 (AN 1,614,134); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Arg924Ser (c.2770C>A)?

POLE p.Arg924Ser (c.2770C>A) is associated with colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Arg924Ser (c.2770C>A) in the general population?

POLE p.Arg924Ser (c.2770C>A) is no allele count reported in gnomAD v4.1 (AN 1,614,134) (gnomAD).

What do computational predictors say about POLE p.Arg924Ser (c.2770C>A)?

AlphaMissense predicts ambiguous (score 0.5615) — an in-silico prediction, not a clinical call.

POLE p.Arg924Ser

c.2770C>A · rs369751686 · VCV540791

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5615 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,134)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

colorectal cancer, susceptibility to, 12

Computational evidence

Protein change
AlphaMissense	0.5615	ambiguous
REVEL	0.114	moderately benign-leaning
SaProt	LLR -9.45	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,961 bp · p 0.18 · regional, not allelic
Overall
CADD	24.6	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

No allele count reported in gnomAD v4.1 (AN 1,614,134). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: POLE
Protein: p.Arg924Ser
Coding: c.2770C>A
MANE Select: NM_006231
dbSNP: rs369751686
Type: single nucleotide variant
Location: chr12:132661621 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 924: a UniProt-annotated variant site (in imagei)

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

Disease context

colorectal cancer, susceptibility to, 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

Similar variants

POLE p.Arg924Cys Uncertain significance ★★ ⚠ same residue
POLE p.Arg924Gly Uncertain significance ★★ ⚠ same residue
POLE p.Arg924His Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg924Leu Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T Pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.1020+5G>A 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-arg924ser (accessed [today's date]).

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