Is POLE p.Phe2104Leu (c.6312C>G) pathogenic?

POLE p.Phe2104Leu (c.6312C>G) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-19). AlphaMissense: likely pathogenic (0.9326); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Phe2104Leu (c.6312C>G)?

POLE p.Phe2104Leu (c.6312C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Phe2104Leu (c.6312C>G) in the general population?

POLE p.Phe2104Leu (c.6312C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLE p.Phe2104Leu (c.6312C>G)?

AlphaMissense predicts likely pathogenic (score 0.9326) — an in-silico prediction, not a clinical call.

POLE p.Phe2104Leu

c.6312C>G · rs1555220869 · VCV540700

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9326 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9326	likely pathogenic
REVEL	0.217	benign-leaning
SaProt	LLR -11.71	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POLE
Protein: p.Phe2104Leu
Coding: c.6312C>G
MANE Select: NM_006231
dbSNP: rs1555220869
Type: single nucleotide variant
Location: chr12:132632333 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2104: 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.Phe2104Ile Uncertain significance ★ ⚠ same residue
POLE p.Phe2104= 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

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-phe2104leu (accessed [today's date]).

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