Is POLE p.Arg259His (c.776G>A) pathogenic?

POLE p.Arg259His (c.776G>A) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 25 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.1598); Low-frequency (popmax 1.19%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg259His (c.776G>A)?

POLE p.Arg259His (c.776G>A) is associated with hereditary neoplastic syndrome, colon carcinoma, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Arg259His (c.776G>A) in the general population?

POLE p.Arg259His (c.776G>A) is low-frequency (popmax 1.19%, nfe) (gnomAD).

What do computational predictors say about POLE p.Arg259His (c.776G>A)?

AlphaMissense predicts likely benign (score 0.1598) — an in-silico prediction, not a clinical call.

POLE p.Arg259His

c.776G>A · rs61732929 · VCV221085

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 25 submitters

AlphaMissense

likely benign

0.1598 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.19%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1598	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -8.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	24.1	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 1.19% European (non-Finnish) · 14,067/1,179,774 alleles

Filtering AF 1.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.17%

Overall 0.94% 15,171/1,613,816 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.19%	84
Amishnot grpmax-eligible	0.877%	114
Remaining individualsnot grpmax-eligible	0.826%	121
Admixed American	0.3%	333
Finnishnot grpmax-eligible	0.295%	339
African / African-American	0.216%	463
South Asian	0.0406%	2,461
East Asian	0.0245%	4,081
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Arg259His
Coding: c.776G>A
MANE Select: NM_006231
dbSNP: rs61732929
Type: single nucleotide variant
Location: chr12:132677388 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 259: 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: colon carcinoma colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Arg259Cys Uncertain significance ★★ ⚠ same residue
POLE p.Arg259Leu Uncertain significance ★★ ⚠ same residue
POLE p.Arg259Gly Uncertain significance ★ same residue
POLE p.Arg259= Likely benign ★ 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-arg259his (accessed [today's date]).

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