Is POLE p.Arg2149Cys (c.6445C>T) pathogenic?

POLE p.Arg2149Cys (c.6445C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0714); Ultra-rare (popmax 0.0428%, sas); Associated with Polymerase proofreading-related adenomatous polyposis.

What condition is associated with POLE p.Arg2149Cys (c.6445C>T)?

POLE p.Arg2149Cys (c.6445C>T) is associated with Polymerase proofreading-related adenomatous polyposis, colorectal cancer, susceptibility to, 12, facial dysmorphism-immunodeficiency-livedo-short stature syndrome (ClinVar).

How common is POLE p.Arg2149Cys (c.6445C>T) in the general population?

POLE p.Arg2149Cys (c.6445C>T) is ultra-rare (popmax 0.0428%, sas) (gnomAD).

How is Polymerase proofreading-related polyposis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about POLE p.Arg2149Cys (c.6445C>T)?

AlphaMissense predicts likely benign (score 0.0714) — an in-silico prediction, not a clinical call.

POLE p.Arg2149Cys

c.6445C>T · rs771490182 · VCV405704

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0714 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0428%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Polymerase proofreading-related adenomatous polyposis

Computational evidence

Protein change
AlphaMissense	0.0714	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -2.63	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 5.8	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	21.3	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 0.0428% South Asian · 39/91,064 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0284%

Overall 0.00657% 106/1,613,790 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0428%	2,335
Middle Eastern	0.0165%	6,054
African / African-American	0.00933%	10,722
Remaining individualsnot grpmax-eligible	0.008%	12,498
Admixed American	0.005%	20,004
European (non-Finnish)	0.00432%	23,136

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.Arg2149Cys
Coding: c.6445C>T
MANE Select: NM_006231
dbSNP: rs771490182
Type: single nucleotide variant
Location: chr12:132626203 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2149: a UniProt-annotated variant site (in imagei)

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

Disease context

Polymerase proofreading-related adenomatous polyposis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer, susceptibility to, 12 facial dysmorphism-immunodeficiency-livedo-short stature syndrome hereditary neoplastic syndrome familial colorectal cancer type X familial colorectal cancer

For Polymerase proofreading-related polyposis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

POLE p.Arg2149His Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg2149Leu Conflicting classifications of pathogenicity ★ ⚠ 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-arg2149cys (accessed [today's date]).

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