Is POLE p.Ala2002Val (c.6005C>T) pathogenic?

POLE p.Ala2002Val (c.6005C>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.5706); Very rare (popmax 0.00034%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala2002Val (c.6005C>T)?

POLE p.Ala2002Val (c.6005C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala2002Val (c.6005C>T) in the general population?

POLE p.Ala2002Val (c.6005C>T) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about POLE p.Ala2002Val (c.6005C>T)?

AlphaMissense predicts likely pathogenic (score 0.5706) — an in-silico prediction, not a clinical call.

POLE p.Ala2002Val

c.6005C>T · rs1247397969 · VCV572677

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5706	likely pathogenic
REVEL	0.206	benign-leaning
SaProt	LLR -8.86	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	24.5	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 0.00034% European (non-Finnish) · 4/1,176,732 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000414% 6/1,450,240 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,106
European (non-Finnish)grpmax	0.00034%	294,183

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala2002Val
Coding: c.6005C>T
MANE Select: NM_006231
dbSNP: rs1247397969
Type: single nucleotide variant
Location: chr12:132632795 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2002: 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.Ala2002= Likely benign ★★ same residue
POLE p.Ala2002Pro Uncertain significance ★ ⚠ same residue
POLE p.Ala2002Thr 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

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-ala2002val (accessed [today's date]).

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