Is POLE p.Phe1030= (c.3090C>T) pathogenic?

POLE p.Phe1030= (c.3090C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0134%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Phe1030= (c.3090C>T)?

POLE p.Phe1030= (c.3090C>T) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Phe1030= (c.3090C>T) in the general population?

POLE p.Phe1030= (c.3090C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

POLE p.Phe1030=

c.3090C>T · rs766306895 · VCV413545

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -3.4
Overall
CADD	4.404	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,894 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.0018% 29/1,613,926 alleles · ultra-rare exomes 25/1,461,764 · genomes 4/152,162 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,482
South Asian	0.00988%	10,118
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Finnishnot grpmax-eligible	0.00313%	31,991
European (non-Finnish)	0.000847%	117,997

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.Phe1030=
Coding: c.3090C>T
MANE Select: NM_006231
dbSNP: rs766306895
Type: single nucleotide variant
Location: chr12:132659480 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1030: an α-helix; 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: colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Phe1030Tyr Uncertain significance ★★ same residue
POLE p.Phe1030Ser Uncertain significance ★ ⚠ same residue
POLE p.Phe1030Cys Uncertain significance ★ ⚠ same residue
POLE p.Phe1030Leu 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
POLE c.1020+5G>A 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-phe1030 (accessed [today's date]).

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