Is POLE p.Arg231Cys (c.691C>T) pathogenic?

POLE p.Arg231Cys (c.691C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.9444); Ultra-rare (popmax 0.0364%, nfe); Associated with Polymerase proofreading-related adenomatous polyposis.

What condition is associated with POLE p.Arg231Cys (c.691C>T)?

POLE p.Arg231Cys (c.691C>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.Arg231Cys (c.691C>T) in the general population?

POLE p.Arg231Cys (c.691C>T) is ultra-rare (popmax 0.0364%, nfe) (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.Arg231Cys (c.691C>T)?

AlphaMissense predicts likely pathogenic (score 0.9444) — an in-silico prediction, not a clinical call.

POLE p.Arg231Cys

c.691C>T · rs146592584 · VCV240623

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.9444 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0364%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Polymerase proofreading-related adenomatous polyposis

Computational evidence

Protein change
AlphaMissense	0.9444	likely pathogenic
REVEL	0.583	indeterminate
SaProt	LLR -14.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	33.0	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 0.0364% European (non-Finnish) · 429/1,180,024 alleles

Filtering AF 0.0335% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0323%

Overall 0.0279% 450/1,614,030 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0364%	2,751
Remaining individualsnot grpmax-eligible	0.024%	4,165
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00333%	30,002
Finnishnot grpmax-eligible	0.00312%	32,015
East Asian	0.00223%	44,896

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.Arg231Cys
Coding: c.691C>T
MANE Select: NM_006231
dbSNP: rs146592584
Type: single nucleotide variant
Location: chr12:132677607 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 231: a UniProt-annotated variant site (found in a colorectal sample; somatic mutation); an α-helix

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 intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

For Polymerase proofreading-related polyposis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

POLE p.Arg231His Uncertain significance ★★ ⚠ same residue
POLE p.Arg231Pro Uncertain significance ★ ⚠ same residue
POLE p.Arg231Leu Uncertain significance ★ ⚠ same residue
POLE p.Arg231Ser Uncertain significance ★ ⚠ 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

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-arg231cys (accessed [today's date]).

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