Is POLE p.Arg2225His (c.6674G>A) pathogenic?

POLE p.Arg2225His (c.6674G>A) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.065); Ultra-rare (popmax 0.02%, amr); Associated with Hereditary cancer.

What condition is associated with POLE p.Arg2225His (c.6674G>A)?

POLE p.Arg2225His (c.6674G>A) is associated with Hereditary cancer, colon carcinoma, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Arg2225His (c.6674G>A) in the general population?

POLE p.Arg2225His (c.6674G>A) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about POLE p.Arg2225His (c.6674G>A)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

POLE p.Arg2225His

c.6674G>A · rs538875477 · VCV240612

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary cancer

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -7.16	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 -5.5
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	11.41	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 0.02% Admixed American · 12/60,026 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00737% 119/1,613,830 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.0112%	8,928
African / African-American	0.00933%	10,723
European (non-Finnish)	0.00763%	13,110
Finnishnot grpmax-eligible	0.00313%	31,901
East Asian	0.00223%	44,878

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.Arg2225His
Coding: c.6674G>A
MANE Select: NM_006231
dbSNP: rs538875477
Type: single nucleotide variant
Location: chr12:132624978 (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

Hereditary cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colon carcinoma colorectal cancer, susceptibility to, 12 facial dysmorphism-immunodeficiency-livedo-short stature syndrome hereditary neoplastic syndrome

Similar variants

POLE p.Arg2225= Benign/Likely benign ★★ same residue
POLE p.Arg2225Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg2225Gly 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-arg2225his (accessed [today's date]).

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