Is POLE p.His580= (c.1740C>T) pathogenic?

POLE p.His580= (c.1740C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-18). Rare (popmax 0.196%, eas); Associated with Polymerase proofreading-related adenomatous polyposis.

What condition is associated with POLE p.His580= (c.1740C>T)?

POLE p.His580= (c.1740C>T) is associated with Polymerase proofreading-related adenomatous polyposis, hereditary neoplastic syndrome, familial colorectal cancer type X (ClinVar).

How common is POLE p.His580= (c.1740C>T) in the general population?

POLE p.His580= (c.1740C>T) is rare (popmax 0.196%, eas) (gnomAD).

How is Polymerase proofreading-related polyposis inherited?

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

POLE p.His580=

c.1740C>T · rs114972594 · VCV386271

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

rare (popmax 0.196%, eas)

Conditions

Polymerase proofreading-related adenomatous polyposis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.4	GERP -3.4
Overall
CADD	0.407	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.196% East Asian · 88/44,888 alleles

Filtering AF 0.163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.00793% 128/1,614,196 alleles · rare exomes 106/1,461,876 · genomes 22/152,320 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.196%	510
Remaining individualsnot grpmax-eligible	0.0224%	4,465
Admixed American	0.0117%	8,575
South Asian	0.00549%	18,217
African / African-American	0.00267%	37,523
European (non-Finnish)	0.00102%	98,336

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.His580=
Coding: c.1740C>T
MANE Select: NM_006231
dbSNP: rs114972594
Type: single nucleotide variant
Location: chr12:132672269 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 580: an α-helix

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

Disease context

Polymerase proofreading-related adenomatous polyposis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome familial colorectal cancer type X

For Polymerase proofreading-related polyposis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

POLE p.His580Asn Uncertain significance ★★ same residue
POLE p.His580Gln Uncertain significance ★ ⚠ same residue
POLE p.His580Leu Uncertain significance ★ ⚠ same residue
POLE p.His580fs Conflicting classifications of pathogenicity ★ same residue
POLE p.His580Arg Uncertain significance ★★ ⚠ same residue
POLE p.His580Tyr Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ 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-his580 (accessed [today's date]).

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