Is POLE p.Phe695Val (c.2083T>G) pathogenic?

POLE p.Phe695Val (c.2083T>G) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-12). AlphaMissense: likely pathogenic (0.5892); Very rare (popmax 0.00668%, afr); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Phe695Val (c.2083T>G)?

POLE p.Phe695Val (c.2083T>G) is associated with colorectal cancer, susceptibility to, 12, facial dysmorphism-immunodeficiency-livedo-short stature syndrome, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Phe695Val (c.2083T>G) in the general population?

POLE p.Phe695Val (c.2083T>G) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about POLE p.Phe695Val (c.2083T>G)?

AlphaMissense predicts likely pathogenic (score 0.5892) — an in-silico prediction, not a clinical call.

POLE p.Phe695Val

c.2083T>G · rs5744799 · VCV560841

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.5892 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

colorectal cancer, susceptibility to, 12

Computational evidence

Protein change
AlphaMissense	0.5892	likely pathogenic
REVEL	0.195	benign-leaning
SaProt	LLR -8.51	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
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	23.9	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 0.00668% African / African-American · 5/74,864 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000806% 13/1,612,366 alleles · very rare exomes 10/1,460,236 · genomes 3/152,130 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,973
East Asian	0.00223%	44,814
South Asian	0.0011%	90,848
European (non-Finnish)	0.000509%	196,522

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.Phe695Val
Coding: c.2083T>G
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

colorectal cancer, susceptibility to, 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: facial dysmorphism-immunodeficiency-livedo-short stature syndrome hereditary neoplastic syndrome intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Similar variants

POLE p.Phe695Cys Uncertain significance ★★ ⚠ same residue
POLE p.Phe695Ile Benign/Likely benign ★★ 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-phe695val (accessed [today's date]).

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