Is POLE p.Ala1150Val (c.3449C>T) pathogenic?

POLE p.Ala1150Val (c.3449C>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-13). AlphaMissense: likely pathogenic (0.6224); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala1150Val (c.3449C>T)?

POLE p.Ala1150Val (c.3449C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala1150Val (c.3449C>T) in the general population?

POLE p.Ala1150Val (c.3449C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about POLE p.Ala1150Val (c.3449C>T)?

AlphaMissense predicts likely pathogenic (score 0.6224) — an in-silico prediction, not a clinical call.

POLE p.Ala1150Val

c.3449C>T · rs2042567693 · VCV2891094

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6224 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6224	likely pathogenic
REVEL	0.542	indeterminate
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	25.9	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 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 0.000657% 1/152,092 alleles · very rare

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.Ala1150Val
Coding: c.3449C>T
MANE Select: NM_006231
dbSNP: rs2042567693
Type: single nucleotide variant
Location: chr12:132657359 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1150: 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.Ala1150Thr Uncertain significance ★ ⚠ same residue
POLE p.Ala1150= 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-ala1150val (accessed [today's date]).

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