Is POLE p.Arg685Trp (c.2053C>T) pathogenic?

POLE p.Arg685Trp (c.2053C>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-09). AlphaMissense: ambiguous (0.4096); Ultra-rare (popmax 0.0223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg685Trp (c.2053C>T)?

POLE p.Arg685Trp (c.2053C>T) is associated with hereditary neoplastic syndrome, Polymerase proofreading-related adenomatous polyposis (ClinVar).

How common is POLE p.Arg685Trp (c.2053C>T) in the general population?

POLE p.Arg685Trp (c.2053C>T) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about POLE p.Arg685Trp (c.2053C>T)?

AlphaMissense predicts ambiguous (score 0.4096) — an in-silico prediction, not a clinical call.

POLE p.Arg685Trp

c.2053C>T · rs116326665 · VCV405614

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4096 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4096	ambiguous
REVEL	0.471	indeterminate
SaProt	LLR -10.36	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.66, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	24.8	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 0.0223% East Asian · 10/44,782 alleles

Filtering AF 0.0129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.00237% 38/1,606,352 alleles · ultra-rare exomes 32/1,454,130 · genomes 6/152,222 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,478
South Asian	0.02%	4,992
African / African-American	0.00401%	24,913
Admixed American	0.00169%	59,116
European (non-Finnish)	0.00051%	196,001

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.Arg685Trp
Coding: c.2053C>T
MANE Select: NM_006231
dbSNP: rs116326665
Type: single nucleotide variant
Location: chr12:132668476 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 685: an α-helix; a UniProt-annotated variant site (in imagei)

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: Polymerase proofreading-related adenomatous polyposis

Similar variants

POLE p.Arg685Gln Uncertain significance ★★ ⚠ same residue
POLE p.Arg685Leu Uncertain significance ★★ ⚠ same residue
POLE p.Arg685Gly Uncertain significance ★ ⚠ same residue
POLE p.Arg685= Likely benign ★ 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-arg685trp (accessed [today's date]).

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