Is POLE p.Pro1247= (c.3741G>A) pathogenic?

POLE p.Pro1247= (c.3741G>A) is classified Likely benign in POLE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-12). Very rare (popmax 0.00769%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Pro1247= (c.3741G>A)?

POLE p.Pro1247= (c.3741G>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Pro1247= (c.3741G>A) in the general population?

POLE p.Pro1247= (c.3741G>A) is very rare (popmax 0.00769%, sas) (gnomAD).

POLE p.Pro1247=

c.3741G>A · rs368978839 · VCV240476

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -0.52
Overall
CADD	4.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,074 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00366% 59/1,614,072 alleles · very rare exomes 55/1,461,874 · genomes 4/152,198 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,011
East Asian	0.00446%	22,446
African / African-American	0.004%	24,973
European (non-Finnish)	0.0039%	25,653
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Pro1247=
Coding: c.3741G>A
MANE Select: NM_006231
dbSNP: rs368978839
Type: single nucleotide variant
Location: chr12:132649731 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1247: 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.Pro1247Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro1247Thr Uncertain significance ★ ⚠ same residue
POLE p.Pro1247Gln Uncertain significance ★ ⚠ same residue
POLE p.Pro1247Ser 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-pro1247 (accessed [today's date]).

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