Is POLE p.Arg231His (c.692G>A) pathogenic?

POLE p.Arg231His (c.692G>A) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.9586); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg231His (c.692G>A)?

POLE p.Arg231His (c.692G>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Arg231His (c.692G>A) in the general population?

POLE p.Arg231His (c.692G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about POLE p.Arg231His (c.692G>A)?

AlphaMissense predicts likely pathogenic (score 0.9586) — an in-silico prediction, not a clinical call.

POLE p.Arg231His

c.692G>A · rs1060500835 · VCV405750

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9586	likely pathogenic
REVEL	0.7	pathogenic-leaning
SaProt	LLR -12.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,614,164 alleles · very rare exomes 5/1,461,878 · genomes 0/152,286 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000254%	393,340

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.Arg231His
Coding: c.692G>A
MANE Select: NM_006231
dbSNP: rs1060500835
Type: single nucleotide variant
Location: chr12:132677606 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLE p.Arg231Cys Conflicting classifications of pathogenicity ★ ⚠ 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 p.Leu424Val Pathogenic ★★ same condition
POLE c.1020+5G>A Uncertain significance ★★ same condition
POLE c.1106+3G>C 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-arg231his (accessed [today's date]).

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