Is POLE p.Phe1215= (c.3645C>T) pathogenic?

POLE p.Phe1215= (c.3645C>T) is classified Likely benign in POLE (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-06). Ultra-rare (popmax 0.0329%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Phe1215= (c.3645C>T)?

POLE p.Phe1215= (c.3645C>T) is associated with hereditary neoplastic syndrome, familial colorectal cancer type X, Polymerase proofreading-related adenomatous polyposis (ClinVar).

How common is POLE p.Phe1215= (c.3645C>T) in the general population?

POLE p.Phe1215= (c.3645C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

POLE p.Phe1215=

c.3645C>T · rs758716323 · VCV473612

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

hereditary neoplastic syndrome

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 -7.9	GERP -3.7
Overall
CADD	0.049	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.00149% 24/1,614,004 alleles · ultra-rare exomes 21/1,461,834 · genomes 3/152,170 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
South Asian	0.00988%	10,120
Remaining individualsnot grpmax-eligible	0.0032%	31,243
East Asian	0.00223%	44,890
Finnishnot grpmax-eligible	0.00156%	63,986
African / African-American	0.00133%	74,918
European (non-Finnish)	0.000678%	147,504

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.Phe1215=
Coding: c.3645C>T
MANE Select: NM_006231
dbSNP: rs758716323
Type: single nucleotide variant
Location: chr12:132649827 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1215: 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

Also linked: familial colorectal cancer type X Polymerase proofreading-related adenomatous polyposis

Similar variants

POLE p.Phe1215Leu Likely benign ★ 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-phe1215 (accessed [today's date]).

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