Is POLE p.Cys794Phe (c.2381G>T) pathogenic?

POLE p.Cys794Phe (c.2381G>T) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.6473); Very rare (popmax 0.00167%, amr).

How common is POLE p.Cys794Phe (c.2381G>T) in the general population?

POLE p.Cys794Phe (c.2381G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about POLE p.Cys794Phe (c.2381G>T)?

AlphaMissense predicts likely pathogenic (score 0.6473) — an in-silico prediction, not a clinical call.

POLE p.Cys794Phe

c.2381G>T · rs2042771973 · VCV1026899

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6473 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6473	likely pathogenic
REVEL	0.45	indeterminate
SaProt	LLR -5.36	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	24.4	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 0.00167% Admixed American · 1/60,020 alleles

Overall 0.000124% 2/1,613,848 alleles · very rare exomes 2/1,461,568 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
European (non-Finnish)	8.47e-05%	1,180,016

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.Cys794Phe
Coding: c.2381G>T
MANE Select: NM_006231
dbSNP: rs2042771973
Type: single nucleotide variant
Location: chr12:132665389 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 794: 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.Cys794Arg Uncertain significance ★★ ⚠ same residue
POLE p.Cys794= Likely benign ★★ same residue
POLE p.Cys794Ser Uncertain significance ★ 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-cys794phe (accessed [today's date]).

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