Is POLE p.Pro700Leu (c.2099C>T) pathogenic?

POLE p.Pro700Leu (c.2099C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-28). AlphaMissense: likely benign (0.0894); Very rare (popmax 0.00669%, amr); Associated with familial colorectal cancer.

What condition is associated with POLE p.Pro700Leu (c.2099C>T)?

POLE p.Pro700Leu (c.2099C>T) is associated with familial colorectal cancer, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Pro700Leu (c.2099C>T) in the general population?

POLE p.Pro700Leu (c.2099C>T) is very rare (popmax 0.00669%, amr) (gnomAD).

What do computational predictors say about POLE p.Pro700Leu (c.2099C>T)?

AlphaMissense predicts likely benign (score 0.0894) — an in-silico prediction, not a clinical call.

POLE p.Pro700Leu

c.2099C>T · rs777002868 · VCV405735

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0894 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial colorectal cancer

Computational evidence

Protein change
AlphaMissense	0.0894	likely benign
REVEL	0.397	indeterminate
SaProt	LLR -9.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	27.4	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 0.00669% Admixed American · 4/59,796 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000558% 9/1,612,748 alleles · very rare exomes 9/1,460,420 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00669%	14,949
Remaining individualsnot grpmax-eligible	0.0016%	62,450
European (non-Finnish)	0.000339%	294,823

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.Pro700Leu
Coding: c.2099C>T
MANE Select: NM_006231
dbSNP: rs777002868
Type: single nucleotide variant
Location: chr12:132668430 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 700: a UniProt-annotated variant site (in imagei)

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

Disease context

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

Also linked: hereditary neoplastic syndrome

Similar variants

POLE p.Pro700= Likely benign ★★ same residue
POLE p.Pro700Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro700fs Uncertain significance ★ same residue
POLE p.Pro700Arg Uncertain significance ★ ⚠ 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-pro700leu (accessed [today's date]).

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