Is POLE p.Phe1667= (c.5001C>T) pathogenic?

POLE p.Phe1667= (c.5001C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-14). Ultra-rare (popmax 0.0107%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Phe1667= (c.5001C>T)?

POLE p.Phe1667= (c.5001C>T) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Phe1667= (c.5001C>T) in the general population?

POLE p.Phe1667= (c.5001C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

POLE p.Phe1667=

c.5001C>T · rs112358554 · VCV484439

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.66
Overall
CADD	8.547	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,480 alleles

Filtering AF 0.00531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00383%

Overall 0.0022% 35/1,588,668 alleles · ultra-rare exomes 32/1,436,450 · genomes 3/152,218 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,310
Remaining individualsnot grpmax-eligible	0.00489%	20,458
Admixed American	0.00347%	28,837
European (non-Finnish)	0.00189%	52,998

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.Phe1667=
Coding: c.5001C>T
MANE Select: NM_006231
dbSNP: rs112358554
Type: single nucleotide variant
Location: chr12:132642349 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1667: 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.Phe1667Leu 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
POLE c.1106+3G>C Uncertain significance ★★ same condition
POLE c.1106+4A>G Uncertain significance ★★ same condition
POLE c.1226+3A>G 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-phe1667 (accessed [today's date]).

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