Is POLE p.Asp339Val (c.1016A>T) pathogenic?

POLE p.Asp339Val (c.1016A>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-03). AlphaMissense: likely pathogenic (0.6515); Very rare (popmax 0.00171%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Asp339Val (c.1016A>T)?

POLE p.Asp339Val (c.1016A>T) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Asp339Val (c.1016A>T) in the general population?

POLE p.Asp339Val (c.1016A>T) is very rare (popmax 0.00171%, amr) (gnomAD).

What do computational predictors say about POLE p.Asp339Val (c.1016A>T)?

AlphaMissense predicts likely pathogenic (score 0.6515) — an in-silico prediction, not a clinical call.

POLE p.Asp339Val

c.1016A>T · rs1060500865 · VCV405828

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.6515 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00171%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6515	likely pathogenic
REVEL	0.496	indeterminate
SaProt	LLR -10.00	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.57 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	25.8	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 0.00171% Admixed American · 1/58,368 alleles

Filtering AF 0.000249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00016%

Overall 0.000553% 8/1,445,688 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00171%	58,368
European (non-Finnish)	0.000599%	166,975

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.Asp339Val
Coding: c.1016A>T
MANE Select: NM_006231
dbSNP: rs1060500865
Type: single nucleotide variant
Location: chr12:132676098 (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

Also linked: colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Asp339Tyr Uncertain significance ★★ ⚠ same residue
POLE p.Asp339= Benign/Likely benign ★★ same residue
POLE p.Asp339Ala Uncertain significance ★ same residue
POLE p.Asp339Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Asp339Gly Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T Pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ 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-asp339val (accessed [today's date]).

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