Is POLE p.Val613Ile (c.1837G>A) pathogenic?

POLE p.Val613Ile (c.1837G>A) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.0752); Ultra-rare (popmax 0.02%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Val613Ile (c.1837G>A)?

POLE p.Val613Ile (c.1837G>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Val613Ile (c.1837G>A) in the general population?

POLE p.Val613Ile (c.1837G>A) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about POLE p.Val613Ile (c.1837G>A)?

AlphaMissense predicts likely benign (score 0.0752) — an in-silico prediction, not a clinical call.

POLE p.Val613Ile

c.1837G>A · rs200471266 · VCV473490

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0752 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0752	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -5.05	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 2.2	GERP -0.73, phastCons 0.99
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	15.46	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 0.02% Admixed American · 12/60,024 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00254% 41/1,614,112 alleles · ultra-rare exomes 36/1,461,840 · genomes 5/152,272 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,002
East Asian	0.00669%	14,959
South Asian	0.00549%	18,216
Finnishnot grpmax-eligible	0.00469%	21,340
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.00136%	73,750
African / African-American	0.00133%	75,034

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.Val613Ile
Coding: c.1837G>A
MANE Select: NM_006231
dbSNP: rs200471266
Type: single nucleotide variant
Location: chr12:132668897 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

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.Val613= Likely benign ★ same residue
POLE p.Val613Phe 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-val613ile (accessed [today's date]).

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