Is POLE p.Pro697Ser (c.2089C>T) pathogenic?

POLE p.Pro697Ser (c.2089C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.063); Low-frequency (popmax 1.47%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Pro697Ser (c.2089C>T)?

POLE p.Pro697Ser (c.2089C>T) is associated with hereditary neoplastic syndrome, breast cancer, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Pro697Ser (c.2089C>T) in the general population?

POLE p.Pro697Ser (c.2089C>T) is low-frequency (popmax 1.47%, afr) (gnomAD).

What do computational predictors say about POLE p.Pro697Ser (c.2089C>T)?

AlphaMissense predicts likely benign (score 0.063) — an in-silico prediction, not a clinical call.

POLE p.Pro697Ser

c.2089C>T · rs5744800 · VCV240422

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.063 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.47%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.063	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	0.114	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 1.47% African / African-American · 1,101/74,980 alleles

Filtering AF 1.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.37%

Overall 0.0843% 1,359/1,612,760 alleles · low-frequency exomes 703/1,460,448 · genomes 656/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.47%	68
Remaining individualsnot grpmax-eligible	0.122%	822
Admixed American	0.117%	854
Middle Eastern	0.0991%	1,009
South Asian	0.0242%	4,131
European (non-Finnish)	0.00695%	14,381
East Asian	0.00446%	22,417

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.Pro697Ser
Coding: c.2089C>T
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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: breast cancer colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Pro697= 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 p.Pro697Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T 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-pro697ser (accessed [today's date]).

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