Is POLE p.Lys110= (c.330G>A) pathogenic?

POLE p.Lys110= (c.330G>A) is classified Likely pathogenic in POLE (ClinVar, Single submitter, 1 submitter). Absent from gnomAD v4.1; Associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.

How common is POLE p.Lys110= (c.330G>A) in the general population?

POLE p.Lys110= (c.330G>A) is absent from gnomAD v4.1 (gnomAD).

POLE p.Lys110=

Q: What condition is associated with POLE p.Lys110= (c.330G>A)?

POLE p.Lys110= (c.330G>A) is associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (ClinVar).

c.330G>A · VCV3767243

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.47	acceptor loss, 44 bp away · masked 0 · deltas
Pangolin	Δ0.55	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4	GERP 1.5, phastCons 1
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POLE
Protein: p.Lys110=
Coding: c.330G>A
MANE Select: NM_006231
Type: single nucleotide variant
Location: chr12:132680178 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 110: a β-strand

Full POLE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLE p.Lys110Glu Uncertain significance ★★ ⚠ same residue
POLE p.Lys110Arg Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5378+4C>T Uncertain significance ★★ same condition
POLE p.Ala1007Pro Uncertain significance ★★ ⚠ same condition
POLE p.Ala1149Val Uncertain significance ★★ ⚠ same condition
POLE p.Ala1323Val Uncertain significance ★★ ⚠ same condition
POLE p.Ala1349Val 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-lys110 (accessed [today's date]).

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