Is POLE p.Arg2165His (c.6494G>A) pathogenic?

POLE p.Arg2165His (c.6494G>A) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1353); Low-frequency (popmax 3.02%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg2165His (c.6494G>A)?

POLE p.Arg2165His (c.6494G>A) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Arg2165His (c.6494G>A) in the general population?

POLE p.Arg2165His (c.6494G>A) is low-frequency (popmax 3.02%, mid) (gnomAD).

What do computational predictors say about POLE p.Arg2165His (c.6494G>A)?

AlphaMissense predicts likely benign (score 0.1353) — an in-silico prediction, not a clinical call.

POLE p.Arg2165His

c.6494G>A · rs5745068 · VCV220837

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

AlphaMissense

likely benign

0.1353 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.02%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1353	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -5.96	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 2.2	phastCons 0.98
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · 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 3.02% Middle Eastern · 177/5,868 alleles

Filtering AF 2.65% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.51%

Overall 0.458% 7,368/1,609,618 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	3.02%	33
South Asian	1.42%	71
Ashkenazi Jewishnot grpmax-eligible	0.915%	109
African / African-American	0.845%	118
Remaining individualsnot grpmax-eligible	0.711%	141
East Asian	0.633%	158
Admixed American	0.352%	284
European (non-Finnish)	0.344%	291
Amishnot grpmax-eligible	0.11%	910
Finnishnot grpmax-eligible	0.033%	3,027

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.Arg2165His
Coding: c.6494G>A
MANE Select: NM_006231
dbSNP: rs5745068
Type: single nucleotide variant
Location: chr12:132626154 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2165: a β-strand; a UniProt-annotated variant site (in imagei); a UniProt-annotated variant site (in)

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.Arg2165Cys Uncertain significance ★★ ⚠ same residue
POLE p.Arg2165= Benign/Likely benign ★★ same residue
POLE p.Arg2165Gly 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
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-arg2165his (accessed [today's date]).

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