Is POLE p.Arg2159Cys (c.6475C>T) pathogenic?

POLE p.Arg2159Cys (c.6475C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-27). AlphaMissense: likely benign (0.0822); Ultra-rare (popmax 0.0111%, eas); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Arg2159Cys (c.6475C>T)?

POLE p.Arg2159Cys (c.6475C>T) is associated with colorectal cancer, susceptibility to, 12, facial dysmorphism-immunodeficiency-livedo-short stature syndrome, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Arg2159Cys (c.6475C>T) in the general population?

POLE p.Arg2159Cys (c.6475C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about POLE p.Arg2159Cys (c.6475C>T)?

AlphaMissense predicts likely benign (score 0.0822) — an in-silico prediction, not a clinical call.

POLE p.Arg2159Cys

c.6475C>T · rs5745067 · VCV505637

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0822 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

colorectal cancer, susceptibility to, 12

Computational evidence

Protein change
AlphaMissense	0.0822	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -8.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	23.9	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 0.0111% East Asian · 5/44,844 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00118% 19/1,612,680 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,969
Admixed American	0.00167%	59,826
Remaining individualsnot grpmax-eligible	0.0016%	62,456
European (non-Finnish)	0.00102%	98,287

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.Arg2159Cys
Coding: c.6475C>T
MANE Select: NM_006231
dbSNP: rs5745067
Type: single nucleotide variant
Location: chr12:132626173 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2159: a turn; a UniProt-annotated variant site (in imagei); a UniProt-annotated variant site (in)

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

Also linked: facial dysmorphism-immunodeficiency-livedo-short stature syndrome hereditary neoplastic syndrome intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Similar variants

POLE p.Arg2159His Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg2159= Likely benign ★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T 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-arg2159cys (accessed [today's date]).

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