Is POLE p.Ala2006= (c.6018C>T) pathogenic?

POLE p.Ala2006= (c.6018C>T) is classified Likely benign in POLE (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0164%, mid); Associated with Polymerase proofreading-related adenomatous polyposis.

What condition is associated with POLE p.Ala2006= (c.6018C>T)?

POLE p.Ala2006= (c.6018C>T) is associated with Polymerase proofreading-related adenomatous polyposis, hereditary neoplastic syndrome, familial colorectal cancer type X (ClinVar).

How common is POLE p.Ala2006= (c.6018C>T) in the general population?

POLE p.Ala2006= (c.6018C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Polymerase proofreading-related polyposis inherited?

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

POLE p.Ala2006=

c.6018C>T · rs111709550 · VCV393042

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Polymerase proofreading-related adenomatous polyposis

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 -1.6
Overall
CADD	4.493	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00845% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00662%

Overall 0.00584% 94/1,608,894 alleles · ultra-rare exomes 87/1,456,738 · genomes 7/152,156 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
South Asian	0.0143%	6,997
European (non-Finnish)	0.00653%	15,319
East Asian	0.00223%	44,866
Remaining individualsnot grpmax-eligible	0.0016%	62,412
African / African-American	0.00134%	74,904

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.Ala2006=
Coding: c.6018C>T
MANE Select: NM_006231
dbSNP: rs111709550
Type: single nucleotide variant
Location: chr12:132632782 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2006: 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

Polymerase proofreading-related adenomatous polyposis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome familial colorectal cancer type X

For Polymerase proofreading-related polyposis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

POLE p.Ala2006Ser Uncertain significance ★★ ⚠ same residue
POLE p.Ala2006Val Uncertain significance ★★ ⚠ same residue
POLE p.Ala2006Thr Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely 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

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-ala2006 (accessed [today's date]).

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