Is POLE p.Phe1856Val (c.5566T>G) pathogenic?

POLE p.Phe1856Val (c.5566T>G) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-29). AlphaMissense: ambiguous (0.5117); Very rare (popmax 0.00134%, afr).

How common is POLE p.Phe1856Val (c.5566T>G) in the general population?

POLE p.Phe1856Val (c.5566T>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about POLE p.Phe1856Val (c.5566T>G)?

AlphaMissense predicts ambiguous (score 0.5117) — an in-silico prediction, not a clinical call.

POLE p.Phe1856Val

c.5566T>G · rs1060500846 · VCV1063404

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Computational evidence

Protein change
AlphaMissense	0.5117	ambiguous
REVEL	0.575	indeterminate
SaProt	LLR -7.32	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	26.0	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

Grpmax group 0.00134% African / African-American · 1/74,816 alleles

Overall 6.2e-05% 1/1,613,462 alleles · very rare exomes 1/1,461,656 · genomes 0/151,806 · joint denominator

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.Phe1856Val
Coding: c.5566T>G
MANE Select: NM_006231
dbSNP: rs1060500846
Type: single nucleotide variant
Location: chr12:132638126 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1856: an α-helix; a UniProt-annotated variant site (in imagei)

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

Similar variants

POLE p.Phe1856= Likely benign ★★ same residue
POLE p.Phe1856Leu Uncertain significance ★ ⚠ same residue
POLE p.Phe1856fs Pathogenic ★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same type
POLE c.3276-1G>C Likely pathogenic ★★ same type
POLE c.5678+1G>T Pathogenic ★★ same type
POLE p.Gln1763Ter Pathogenic/Likely pathogenic ★★ same type
POLE p.Leu424Val Pathogenic ★★ same type

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-phe1856val (accessed [today's date]).

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