Is POLE p.Ala1498= (c.4494G>A) pathogenic?

POLE p.Ala1498= (c.4494G>A) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-16). Ultra-rare (popmax 0.03%, amr); Associated with familial colorectal cancer type X.

What condition is associated with POLE p.Ala1498= (c.4494G>A)?

POLE p.Ala1498= (c.4494G>A) is associated with familial colorectal cancer type X, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala1498= (c.4494G>A) in the general population?

POLE p.Ala1498= (c.4494G>A) is ultra-rare (popmax 0.03%, amr) (gnomAD).

How is Familial colorectal cancer Type X inherited?

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

POLE p.Ala1498=

c.4494G>A · rs777611171 · VCV240521

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Conditions

familial colorectal cancer type X

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 -15	GERP -3.5
Overall
CADD	0.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/60,014 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.0031% 50/1,613,834 alleles · ultra-rare exomes 47/1,461,600 · genomes 3/152,234 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,334
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0096%	10,414
European (non-Finnish)	0.00203%	49,169
African / African-American	0.00133%	74,936

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.Ala1498=
Coding: c.4494G>A
MANE Select: NM_006231
dbSNP: rs777611171
Type: single nucleotide variant
Location: chr12:132643281 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1498: a β-strand; a UniProt-annotated variant site (in imagei)

Full POLE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial colorectal cancer type X — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Familial colorectal cancer Type X (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

POLE p.Ala1498Thr Uncertain significance ★★ ⚠ same residue
POLE p.Ala1498Val Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ala1498Glu 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-ala1498 (accessed [today's date]).

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