Is POLE p.His684Arg (c.2051A>G) pathogenic?

POLE p.His684Arg (c.2051A>G) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-13). AlphaMissense: likely benign (0.1425); Very rare (popmax 0.00403%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.His684Arg (c.2051A>G)?

POLE p.His684Arg (c.2051A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.His684Arg (c.2051A>G) in the general population?

POLE p.His684Arg (c.2051A>G) is very rare (popmax 0.00403%, afr) (gnomAD).

What do computational predictors say about POLE p.His684Arg (c.2051A>G)?

AlphaMissense predicts likely benign (score 0.1425) — an in-silico prediction, not a clinical call.

POLE p.His684Arg

c.2051A>G · rs369127106 · VCV566531

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1425 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00403%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1425	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -4.62	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 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00403% African / African-American · 3/74,498 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000497%

Overall 0.000249% 4/1,603,628 alleles · very rare exomes 3/1,451,662 · genomes 1/151,966 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00403%	24,833
European (non-Finnish)	8.51e-05%	1,174,580

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.His684Arg
Coding: c.2051A>G
MANE Select: NM_006231
dbSNP: rs369127106
Type: single nucleotide variant
Location: chr12:132668478 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 684: an α-helix; 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

Similar variants

POLE p.His684Leu Uncertain significance ★★ ⚠ same residue
POLE p.His684Tyr 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
POLE c.1106+4A>G Uncertain significance ★★ same condition
POLE c.1226+3A>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-his684arg (accessed [today's date]).

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