Is POLE p.Ala1885= (c.5655T>C) pathogenic?

POLE p.Ala1885= (c.5655T>C) is classified Likely benign in POLE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-22). Very rare (popmax 0.00534%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala1885= (c.5655T>C)?

POLE p.Ala1885= (c.5655T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala1885= (c.5655T>C) in the general population?

POLE p.Ala1885= (c.5655T>C) is very rare (popmax 0.00534%, afr) (gnomAD).

POLE p.Ala1885=

c.5655T>C · rs761429503 · VCV473752

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, 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 · A>C here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.7	phastCons 1
Overall
CADD	4.434	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,902 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,613,932 alleles · very rare exomes 2/1,461,768 · genomes 3/152,164 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,726
Remaining individualsnot grpmax-eligible	0.0016%	62,470

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.Ala1885=
Coding: c.5655T>C
MANE Select: NM_006231
dbSNP: rs761429503
Type: single nucleotide variant
Location: chr12:132638037 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1885: 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

Similar variants

POLE p.Ala1885Pro Uncertain significance ★★ same residue
POLE p.Ala1885Ser Uncertain significance ★★ ⚠ same residue
POLE p.Ala1885Thr Uncertain significance ★★ ⚠ same residue
POLE p.Ala1885Val Uncertain significance ★★ ⚠ same residue
POLE p.Ala1885Gly 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

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-ala1885 (accessed [today's date]).

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