Is POLE p.Ala1778= (c.5334C>T) pathogenic?

POLE p.Ala1778= (c.5334C>T) is classified Benign in POLE (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). Common (popmax 8.42%, eas) — too common for a highly-penetrant pathogenic allele; Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Ala1778= (c.5334C>T)?

POLE p.Ala1778= (c.5334C>T) is associated with colorectal cancer, susceptibility to, 12, endometrial carcinoma, hereditary neoplastic syndrome (ClinVar).

POLE p.Ala1778=

Q: How common is POLE p.Ala1778= (c.5334C>T) in the general population?

POLE p.Ala1778= (c.5334C>T) is common (popmax 8.42%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.5334C>T · rs11146986 · VCV380429

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 8.42%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

colorectal cancer, susceptibility to, 12

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 0.039	phastCons 0.085
Overall
CADD	2.828	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.42% East Asian · 3,779/44,870 alleles

Filtering AF 8.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.11%

Overall 0.274% 4,422/1,613,910 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	8.42%	12
South Asian	0.343%	292
Remaining individualsnot grpmax-eligible	0.325%	308
Middle Eastern	0.099%	1,010
African / African-American	0.028%	3,574
Admixed American	0.015%	6,669
European (non-Finnish)	0.00771%	12,967
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Ala1778=
Coding: c.5334C>T
MANE Select: NM_006231
dbSNP: rs11146986
Type: single nucleotide variant
Location: chr12:132641691 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1778: a UniProt-annotated variant site (in imagei)

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: endometrial carcinoma hereditary neoplastic syndrome

Similar variants

POLE p.Ala1778Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ala1778Val Conflicting classifications of pathogenicity ★ ⚠ 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

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-ala1778 (accessed [today's date]).

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