Is POLE p.Phe695Ile (c.2083T>A) pathogenic?

POLE p.Phe695Ile (c.2083T>A) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-07-01). AlphaMissense: ambiguous (0.4482); Low-frequency (popmax 1.64%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Phe695Ile (c.2083T>A)?

POLE p.Phe695Ile (c.2083T>A) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Phe695Ile (c.2083T>A) in the general population?

POLE p.Phe695Ile (c.2083T>A) is low-frequency (popmax 1.64%, nfe) (gnomAD).

What do computational predictors say about POLE p.Phe695Ile (c.2083T>A)?

AlphaMissense predicts ambiguous (score 0.4482) — an in-silico prediction, not a clinical call.

POLE p.Phe695Ile

c.2083T>A · rs5744799 · VCV221179

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

AlphaMissense

ambiguous

0.4482 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.64%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4482	ambiguous
REVEL	0.191	benign-leaning
SaProt	LLR -7.31	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	22.3	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 1.64% European (non-Finnish) · 19,328/1,179,112 alleles

Filtering AF 1.62% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.61%

Overall 1.47% 23,624/1,612,464 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.03%	49
European (non-Finnish)grpmax	1.64%	61
South Asian	1.6%	62
Middle Eastern	1.47%	68
Remaining individualsnot grpmax-eligible	1.32%	76
Admixed American	1.05%	95
Finnishnot grpmax-eligible	0.752%	133
African / African-American	0.279%	359
East Asian	0.0067%	14,934

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe695Ile
Coding: c.2083T>A
MANE Select: NM_006231
dbSNP: rs5744799
Type: single nucleotide variant
Location: chr12:132668446 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 695: a UniProt-annotated variant site (in imagei); a UniProt-annotated variant site (in)

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: colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Phe695Cys Uncertain significance ★★ ⚠ same residue
POLE p.Phe695Val Uncertain significance ★★ ⚠ same residue
POLE p.Phe695= Conflicting classifications of pathogenicity ★ same residue
POLE p.Phe695Leu Uncertain significance ★ ⚠ same residue
POLE p.Phe695Ser Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T Pathogenic ★★ same condition
POLE p.Leu424Val 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-phe695ile (accessed [today's date]).

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