Is POLE p.Arg222= (c.666C>G) pathogenic?

POLE p.Arg222= (c.666C>G) is classified Likely benign in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-08). Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg222= (c.666C>G)?

POLE p.Arg222= (c.666C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Arg222= (c.666C>G) in the general population?

POLE p.Arg222= (c.666C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

POLE p.Arg222=

c.666C>G · rs1357052511 · VCV1754771

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.82 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5.6	GERP -3.7
Overall
CADD	0.371	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Overall 0.000124% 2/1,614,106 alleles · very rare exomes 2/1,461,846 · genomes 0/152,260 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
European (non-Finnish)	8.47e-05%	1,179,990

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.Arg222=
Coding: c.666C>G
MANE Select: NM_006231
dbSNP: rs1357052511
Type: single nucleotide variant
Location: chr12:132677632 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 222: 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

Similar variants

POLE p.Arg222Gly Uncertain significance ★★ ⚠ same residue
POLE p.Arg222His Uncertain significance ★★ ⚠ same residue
POLE p.Arg222Ser Uncertain significance ★★ ⚠ same residue
POLE p.Arg222Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely 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-arg222 (accessed [today's date]).

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