Is POLE p.Val835Ile (c.2503G>A) pathogenic?

POLE p.Val835Ile (c.2503G>A) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: ambiguous (0.4275); Very rare (popmax 0.000339%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Val835Ile (c.2503G>A)?

POLE p.Val835Ile (c.2503G>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Val835Ile (c.2503G>A) in the general population?

POLE p.Val835Ile (c.2503G>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about POLE p.Val835Ile (c.2503G>A)?

AlphaMissense predicts ambiguous (score 0.4275) — an in-silico prediction, not a clinical call.

POLE p.Val835Ile

c.2503G>A · rs1013082648 · VCV473536

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4275 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4275	ambiguous
REVEL	0.307	indeterminate
SaProt	LLR -9.53	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 336 bp · p 1.8e-05 · regional, not allelic
Overall
CADD	27.5	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 0.000339% European (non-Finnish) · 4/1,180,036 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,066 alleles · very rare exomes 4/1,461,762 · genomes 0/152,304 · joint denominator

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.Val835Ile
Coding: c.2503G>A
MANE Select: NM_006231
dbSNP: rs1013082648
Type: single nucleotide variant
Location: chr12:132664428 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 835: 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.Val835= Conflicting classifications of pathogenicity ★ same residue
POLE p.Val835Asp 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-val835ile (accessed [today's date]).

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