Is CUL3 p.Lys459= (c.1377G>A) pathogenic?

CUL3 p.Lys459= (c.1377G>A) is classified Likely pathogenic in CUL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-09-29). Absent from gnomAD v4.1; Associated with pseudohypoaldosteronism type 2A.

What condition is associated with CUL3 p.Lys459= (c.1377G>A)?

CUL3 p.Lys459= (c.1377G>A) is associated with pseudohypoaldosteronism type 2A (ClinVar).

How common is CUL3 p.Lys459= (c.1377G>A) in the general population?

CUL3 p.Lys459= (c.1377G>A) is absent from gnomAD v4.1 (gnomAD).

How is Pseudohypoaldosteronism type 2 inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CUL3 p.Lys459=

c.1377G>A · rs886038765 · VCV266041

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

pseudohypoaldosteronism type 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.77	donor loss · deltas
Pangolin	Δ0.69	loss · gain 0.22 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Overall
CADD	23.8	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: CUL3
Protein: p.Lys459=
Coding: c.1377G>A
MANE Select: NM_003590
dbSNP: rs886038765
Type: single nucleotide variant
Location: chr2:224503652 (GRCh38)
Gene constraint: LOEUF 0.365 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.68 · 31 PDB
Residue 459: a UniProt-annotated variant site (in pha2e)

Full CUL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pseudohypoaldosteronism type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pseudohypoaldosteronism type 2 (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

CUL3 p.Lys459Arg Pathogenic same residue
CUL3 p.Lys459Met Pathogenic ★ same residue
CUL3 p.Lys459Thr Uncertain significance ★ ⚠ same residue
CUL3 c.1207-26A>G Pathogenic ★ same condition
CUL3 p.Asp413Gly Likely pathogenic ★ same condition
CUL3 c.1377+3A>G Uncertain significance ★ same condition
CUL3 c.1207-12T>G Pathogenic same condition
CUL3 c.1207-1G>A Pathogenic 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/cul3-p-lys459 (accessed [today's date]).

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