Is POLE p.Pro697Thr (c.2089C>A) pathogenic?

POLE p.Pro697Thr (c.2089C>A) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-20). AlphaMissense: likely benign (0.0998); Very rare (popmax 0.0044%, sas); Associated with POLE-related disorder.

What condition is associated with POLE p.Pro697Thr (c.2089C>A)?

POLE p.Pro697Thr (c.2089C>A) is associated with POLE-related disorder, colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Pro697Thr (c.2089C>A) in the general population?

POLE p.Pro697Thr (c.2089C>A) is very rare (popmax 0.0044%, sas) (gnomAD).

What do computational predictors say about POLE p.Pro697Thr (c.2089C>A)?

AlphaMissense predicts likely benign (score 0.0998) — an in-silico prediction, not a clinical call.

POLE p.Pro697Thr

c.2089C>A · rs5744800 · VCV220705

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0044%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

POLE-related disorder

Computational evidence

Protein change
AlphaMissense	0.0998	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -11.68	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.9	GERP -3.7
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	0.263	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 0.0044% South Asian · 4/90,882 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00192% 31/1,612,652 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0044%	22,721
African / African-American	0.00401%	24,955
Admixed American	0.00334%	29,896
European (non-Finnish)	0.00187%	53,604

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.Pro697Thr
Coding: c.2089C>A
MANE Select: NM_006231
dbSNP: rs5744800
Type: single nucleotide variant
Location: chr12:132668440 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 697: a UniProt-annotated variant site (in imagei)

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

Disease context

POLE-related disorder

Also linked: colorectal cancer, susceptibility to, 12 hereditary neoplastic syndrome

Similar variants

POLE p.Pro697= Likely benign ★★ same residue
POLE p.Pro697Ser Benign/Likely benign ★★ same residue
POLE p.Pro697Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro697Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro697His Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro697Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.3276-1G>C Likely pathogenic ★★ 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-pro697thr (accessed [today's date]).

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