Is POLE p.Ala2002Thr (c.6004G>A) pathogenic?

POLE p.Ala2002Thr (c.6004G>A) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-15). AlphaMissense: ambiguous (0.3537); Very rare (popmax 0.00111%, sas).

How common is POLE p.Ala2002Thr (c.6004G>A) in the general population?

POLE p.Ala2002Thr (c.6004G>A) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about POLE p.Ala2002Thr (c.6004G>A)?

AlphaMissense predicts ambiguous (score 0.3537) — an in-silico prediction, not a clinical call.

POLE p.Ala2002Thr

c.6004G>A · rs1262266978 · VCV2911280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3537 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3537	ambiguous
REVEL	0.159	moderately benign-leaning
SaProt	LLR -6.06	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	27.0	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 0.00111% South Asian · 1/90,350 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000497% 8/1,610,210 alleles · very rare exomes 8/1,457,832 · genomes 0/152,378 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,350
European (non-Finnish)	0.000594%	168,259

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.Ala2002Thr
Coding: c.6004G>A
MANE Select: NM_006231
dbSNP: rs1262266978
Type: single nucleotide variant
Location: chr12:132634186 (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

Similar variants

POLE p.Ala2002Val Uncertain significance ★★ ⚠ same residue
POLE p.Ala2002= Likely benign ★★ same residue
POLE p.Ala2002Pro Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same type
POLE c.3276-1G>C Likely pathogenic ★★ same type
POLE c.5678+1G>T Pathogenic ★★ same type
POLE p.Gln1763Ter Pathogenic/Likely pathogenic ★★ same type
POLE p.Leu424Val Pathogenic ★★ same type

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-ala2002thr (accessed [today's date]).

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