Is POLE p.Ile635= (c.1905C>T) pathogenic?

POLE p.Ile635= (c.1905C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-31). Ultra-rare (popmax 0.0305%, nfe); Associated with Polymerase proofreading-related adenomatous polyposis.

How common is POLE p.Ile635= (c.1905C>T) in the general population?

POLE p.Ile635= (c.1905C>T) is ultra-rare (popmax 0.0305%, nfe) (gnomAD).

How is Polymerase proofreading-related polyposis inherited?

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

POLE p.Ile635=

Q: What condition is associated with POLE p.Ile635= (c.1905C>T)?

POLE p.Ile635= (c.1905C>T) is associated with Polymerase proofreading-related adenomatous polyposis, hereditary neoplastic syndrome (ClinVar).

c.1905C>T · rs145203544 · VCV240411

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0305%, nfe)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.52, phastCons 1
Overall
CADD	7.176	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0305% European (non-Finnish) · 360/1,180,028 alleles

Filtering AF 0.0279% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0268%

Overall 0.0229% 370/1,614,072 alleles · ultra-rare exomes 358/1,461,870 · genomes 12/152,202 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0305%	3,278
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Finnishnot grpmax-eligible	0.00312%	32,020
Admixed American	0.00167%	60,008

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.Ile635=
Coding: c.1905C>T
MANE Select: NM_006231
dbSNP: rs145203544
Type: single nucleotide variant
Location: chr12:132668829 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 635: 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

For Polymerase proofreading-related polyposis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

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
POLE c.1474-3C>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-ile635 (accessed [today's date]).

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