Is POLE p.Arg1508His (c.4523G>A) pathogenic?

POLE p.Arg1508His (c.4523G>A) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 24 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1022); Rare (popmax 0.215%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg1508His (c.4523G>A)?

POLE p.Arg1508His (c.4523G>A) is associated with hereditary neoplastic syndrome, colon carcinoma, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Arg1508His (c.4523G>A) in the general population?

POLE p.Arg1508His (c.4523G>A) is rare (popmax 0.215%, nfe) (gnomAD).

What do computational predictors say about POLE p.Arg1508His (c.4523G>A)?

AlphaMissense predicts likely benign (score 0.1022) — an in-silico prediction, not a clinical call.

POLE p.Arg1508His

c.4523G>A · rs142508245 · VCV240525

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 24 submitters

AlphaMissense

likely benign

0.1022 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.215%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1022	likely benign
REVEL	0.285	benign-leaning
SaProt	LLR -5.87	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 3.3	GERP 0.68, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	21.6	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 0.215% European (non-Finnish) · 2,540/1,180,004 alleles

Filtering AF 0.208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.205%

Overall 0.178% 2,874/1,613,782 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.215%	465
African / African-American	0.209%	478
Remaining individualsnot grpmax-eligible	0.125%	801
Admixed American	0.0999%	1,001
Ashkenazi Jewishnot grpmax-eligible	0.0777%	1,287
Finnishnot grpmax-eligible	0.0204%	4,896
South Asian	0.00329%	30,362

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.Arg1508His
Coding: c.4523G>A
MANE Select: NM_006231
dbSNP: rs142508245
Type: single nucleotide variant
Location: chr12:132643252 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1508: 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

Also linked: colon carcinoma colorectal cancer, susceptibility to, 12 facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Similar variants

POLE p.Arg1508Cys Uncertain significance ★★ ⚠ same residue
POLE p.Arg1508Gly Uncertain significance ★★ ⚠ same residue
POLE p.Arg1508Leu Uncertain significance ★★ ⚠ same residue
POLE p.Arg1508= 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

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-arg1508his (accessed [today's date]).

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