Is POLE p.Pro697Leu (c.2090C>T) pathogenic?

POLE p.Pro697Leu (c.2090C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1389); Ultra-rare (popmax 0.0218%, nfe); Associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome.

What condition is associated with POLE p.Pro697Leu (c.2090C>T)?

POLE p.Pro697Leu (c.2090C>T) is associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome, colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Pro697Leu (c.2090C>T) in the general population?

POLE p.Pro697Leu (c.2090C>T) is ultra-rare (popmax 0.0218%, nfe) (gnomAD).

What do computational predictors say about POLE p.Pro697Leu (c.2090C>T)?

AlphaMissense predicts likely benign (score 0.1389) — an in-silico prediction, not a clinical call.

POLE p.Pro697Leu

Q: How is Facial dysmorphism-immunodeficiency-livedo-short stature syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2090C>T · rs36120395 · VCV405654

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1389 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Computational evidence

Protein change
AlphaMissense	0.1389	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -13.68	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 9.9	GERP 0.82, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	24.0	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 0.0218% European (non-Finnish) · 257/1,179,318 alleles

Filtering AF 0.0196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.0162% 262/1,612,688 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0218%	4,589
Remaining individualsnot grpmax-eligible	0.00641%	15,607
Admixed American	0.00167%	59,796

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.Pro697Leu
Coding: c.2090C>T
MANE Select: NM_006231
dbSNP: rs36120395
Type: single nucleotide variant
Location: chr12:132668439 (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

facial dysmorphism-immunodeficiency-livedo-short stature syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

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.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-pro697leu (accessed [today's date]).

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