Is POLE p.Ser30Ter (c.89C>A) pathogenic?

POLE p.Ser30Ter (c.89C>A) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-02). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ser30Ter (c.89C>A)?

POLE p.Ser30Ter (c.89C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ser30Ter (c.89C>A) in the general population?

POLE p.Ser30Ter (c.89C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

POLE p.Ser30Ter

c.89C>A · rs997586826 · VCV1423169

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

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

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 49
Splicing
SpliceAI	Δ0.47	acceptor gain · deltas
Pangolin	Δ0.41	loss · gain 0.17 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.2e-05% 1/1,614,168 alleles · very rare exomes 1/1,461,850 · genomes 0/152,318 · joint denominator

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.Ser30Ter
Coding: c.89C>A
MANE Select: NM_006231
dbSNP: rs997586826
Type: single nucleotide variant
Location: chr12:132681253 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 30: the 'disordered' region; 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

Similar variants

POLE p.Ser30Leu Uncertain significance ★★ ⚠ same residue
POLE p.Ser30= Likely benign ★★ same residue
POLE p.Ser30Pro Uncertain significance ★ ⚠ same residue
POLE p.Ser30Ala 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

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-ser30ter (accessed [today's date]).

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