Is POLE p.Ile834= (c.2502C>T) pathogenic?

POLE p.Ile834= (c.2502C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-21). Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ile834= (c.2502C>T)?

POLE p.Ile834= (c.2502C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ile834= (c.2502C>T) in the general population?

POLE p.Ile834= (c.2502C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

POLE p.Ile834=

c.2502C>T · rs769459883 · VCV484454

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.43	acceptor gain · deltas
Pangolin	Δ0.30	gain · loss 0.10 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -6	GERP -3.1
Overall
CADD	13.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,896 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000682% 11/1,613,936 alleles · very rare exomes 8/1,461,760 · genomes 3/152,176 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
African / African-American	0.00133%	74,920
European (non-Finnish)	0.000763%	131,113

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.Ile834=
Coding: c.2502C>T
MANE Select: NM_006231
dbSNP: rs769459883
Type: single nucleotide variant
Location: chr12:132664429 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 834: 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.Ile834Val 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
POLE c.1226+3A>G Uncertain significance ★★ same condition
POLE c.1359+4C>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-ile834 (accessed [today's date]).

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