Is POLE p.Arg260Gln (c.779G>A) pathogenic?

POLE p.Arg260Gln (c.779G>A) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.2512); Rare (popmax 0.954%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg260Gln (c.779G>A)?

POLE p.Arg260Gln (c.779G>A) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Arg260Gln (c.779G>A) in the general population?

POLE p.Arg260Gln (c.779G>A) is rare (popmax 0.954%, afr) (gnomAD).

What do computational predictors say about POLE p.Arg260Gln (c.779G>A)?

AlphaMissense predicts likely benign (score 0.2512) — an in-silico prediction, not a clinical call.

POLE p.Arg260Gln

c.779G>A · rs5744752 · VCV220642

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.2512 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.954%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2512	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -11.57	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.45, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	24.0	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

Grpmax group 0.954% African / African-American · 716/75,024 alleles

Filtering AF 0.896% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.873%

Overall 0.0601% 970/1,614,004 alleles · rare exomes 529/1,461,724 · genomes 441/152,280 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.954%	105
Middle Eastern	0.132%	758
Admixed American	0.09%	1,111
Remaining individualsnot grpmax-eligible	0.0816%	1,226
European (non-Finnish)	0.0115%	8,676
East Asian	0.00446%	22,442
South Asian	0.00329%	30,361

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: POLE
Protein: p.Arg260Gln
Coding: c.779G>A
MANE Select: NM_006231
dbSNP: rs5744752
Type: single nucleotide variant
Location: chr12:132677385 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 260: a UniProt-annotated variant site (in); a β-strand

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

Also linked: colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Arg260= Likely benign ★★ same residue
POLE p.Arg260Gly Uncertain significance ★ ⚠ same residue
POLE p.Arg260Ter Conflicting classifications of pathogenicity ★ 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
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-arg260gln (accessed [today's date]).

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