Is POLE p.Arg2225= (c.6675C>T) pathogenic?

POLE p.Arg2225= (c.6675C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-02-04). Rare (popmax 0.261%, nfe); Associated with familial colorectal cancer type X.

What condition is associated with POLE p.Arg2225= (c.6675C>T)?

POLE p.Arg2225= (c.6675C>T) is associated with familial colorectal cancer type X, colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Arg2225= (c.6675C>T) in the general population?

POLE p.Arg2225= (c.6675C>T) is rare (popmax 0.261%, nfe) (gnomAD).

How is Familial colorectal cancer Type X inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

POLE p.Arg2225=

c.6675C>T · rs149973644 · VCV220842

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

gnomAD v4.1

Rare

rare (popmax 0.261%, nfe)

Conditions

familial colorectal cancer type X

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4
Overall
CADD	2.138	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.261% European (non-Finnish) · 3,084/1,179,886 alleles

Filtering AF 0.254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.25%

Overall 0.21% 3,387/1,613,792 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.261%	383
Remaining individualsnot grpmax-eligible	0.235%	425
South Asian	0.0813%	1,231
Middle Eastern	0.066%	1,515
Admixed American	0.0433%	2,308
African / African-American	0.04%	2,502
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
Finnishnot grpmax-eligible	0.0219%	4,558
East Asian	0.00223%	44,882

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.Arg2225=
Coding: c.6675C>T
MANE Select: NM_006231
dbSNP: rs149973644
Type: single nucleotide variant
Location: chr12:132624977 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2225: a UniProt-annotated variant site (in imagei)

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

Disease context

familial colorectal cancer type X — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer, susceptibility to, 12 hereditary neoplastic syndrome Polymerase proofreading-related adenomatous polyposis

For Familial colorectal cancer Type X (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

POLE p.Arg2225Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg2225Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg2225His 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-arg2225 (accessed [today's date]).

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