Is POLE p.Phe335Ser (c.1004T>C) pathogenic?

POLE p.Phe335Ser (c.1004T>C) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-09). AlphaMissense: likely pathogenic (0.8589); No allele count reported in gnomAD v4.1 (AN 1,606,702); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Phe335Ser (c.1004T>C)?

POLE p.Phe335Ser (c.1004T>C) is associated with colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Phe335Ser (c.1004T>C) in the general population?

POLE p.Phe335Ser (c.1004T>C) is no allele count reported in gnomAD v4.1 (AN 1,606,702) (gnomAD).

What do computational predictors say about POLE p.Phe335Ser (c.1004T>C)?

AlphaMissense predicts likely pathogenic (score 0.8589) — an in-silico prediction, not a clinical call.

POLE p.Phe335Ser

c.1004T>C · rs1593078268 · VCV3240169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8589 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,606,702)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

colorectal cancer, susceptibility to, 12

Computational evidence

Protein change
AlphaMissense	0.8589	likely pathogenic
REVEL	0.458	indeterminate
SaProt	LLR -11.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,606,702). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: POLE
Protein: p.Phe335Ser
Coding: c.1004T>C
MANE Select: NM_006231
dbSNP: rs1593078268
Type: single nucleotide variant
Location: chr12:132676110 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 335: a β-strand

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

Disease context

colorectal cancer, susceptibility to, 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLE p.Phe335Cys Uncertain significance ★★ ⚠ same residue
POLE p.Phe335= Likely benign ★★ same residue
POLE p.Phe335Ile Uncertain significance ★ ⚠ same residue
POLE c.5678+1G>T Pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.5378+4C>T Uncertain significance ★★ same condition
POLE p.Ala107Val Uncertain significance ★★ ⚠ same condition
POLE p.Ala1149Val 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-phe335ser (accessed [today's date]).

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