Is POLE p.Thr757= (c.2271C>G) pathogenic?

POLE p.Thr757= (c.2271C>G) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-06). Very rare (popmax 0.000169%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Thr757= (c.2271C>G)?

POLE p.Thr757= (c.2271C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Thr757= (c.2271C>G) in the general population?

POLE p.Thr757= (c.2271C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

POLE p.Thr757=

c.2271C>G · rs765532123 · VCV1788789

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.59	donor gain · deltas
Pangolin	Δ0.26	gain · loss 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -13	GERP -3.7
Overall
CADD	5.016	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,960 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,890 alleles · very rare exomes 2/1,461,870 · genomes 0/152,020 · joint denominator

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.Thr757=
Coding: c.2271C>G
MANE Select: NM_006231
dbSNP: rs765532123
Type: single nucleotide variant
Location: chr12:132667551 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 757: 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.Thr757Ala Uncertain significance ★★ ⚠ same residue
POLE p.Thr757Ile Uncertain significance ★★ ⚠ same residue
POLE p.Thr757Asn 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-thr757 (accessed [today's date]).

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