Is POLE p.Cys1992Phe (c.5975G>T) pathogenic?

POLE p.Cys1992Phe (c.5975G>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-08). AlphaMissense: likely pathogenic (0.7187); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Cys1992Phe (c.5975G>T)?

POLE p.Cys1992Phe (c.5975G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Cys1992Phe (c.5975G>T) in the general population?

POLE p.Cys1992Phe (c.5975G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about POLE p.Cys1992Phe (c.5975G>T)?

AlphaMissense predicts likely pathogenic (score 0.7187) — an in-silico prediction, not a clinical call.

POLE p.Cys1992Phe

c.5975G>T · rs1593711885 · VCV640921

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7187	likely pathogenic
REVEL	0.611	indeterminate
SaProt	LLR -7.48	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	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	26.5	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 8.48e-05% European (non-Finnish) · 1/1,179,694 alleles

Overall 6.2e-05% 1/1,613,516 alleles · very rare exomes 0/1,461,254 · genomes 1/152,262 · 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.Cys1992Phe
Coding: c.5975G>T
MANE Select: NM_006231
dbSNP: rs1593711885
Type: single nucleotide variant
Location: chr12:132634215 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1992: 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.Cys1992Gly Uncertain significance ★★ ⚠ same residue
POLE p.Cys1992= Likely benign ★★ same residue
POLE p.Cys1992Arg Uncertain significance ★ ⚠ 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

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-cys1992phe (accessed [today's date]).

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