Is POLE p.Val351Ile (c.1051G>A) pathogenic?

POLE p.Val351Ile (c.1051G>A) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.0589); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Val351Ile (c.1051G>A)?

POLE p.Val351Ile (c.1051G>A) is associated with hereditary neoplastic syndrome, POLD1-related polyposis and colorectal cancer syndrome (ClinVar).

How common is POLE p.Val351Ile (c.1051G>A) in the general population?

POLE p.Val351Ile (c.1051G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about POLE p.Val351Ile (c.1051G>A)?

AlphaMissense predicts likely benign (score 0.0589) — an in-silico prediction, not a clinical call.

POLE p.Val351Ile

c.1051G>A · rs759414746 · VCV240373

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0589 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0589	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -4.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.54 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.11	GERP -3.3
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	6.306	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 0.00223% East Asian · 1/44,894 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00124% 20/1,614,028 alleles · very rare exomes 19/1,461,832 · genomes 1/152,196 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
South Asian	0.0022%	45,545
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,480
Finnishnot grpmax-eligible	0.00156%	64,042
European (non-Finnish)	0.00119%	84,286

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.Val351Ile
Coding: c.1051G>A
MANE Select: NM_006231
dbSNP: rs759414746
Type: single nucleotide variant
Location: chr12:132675790 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 351: an α-helix

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: POLD1-related polyposis and colorectal cancer syndrome

Similar variants

POLE p.Val351Phe Uncertain significance ★★ ⚠ same residue
POLE p.Val351= Likely benign ★ 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-val351ile (accessed [today's date]).

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