Is CUL3 p.Leu165fs (c.493_494del) pathogenic?

CUL3 p.Leu165fs (c.493494del) is classified Pathogenic/Likely pathogenic in CUL3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-04-24). Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with CUL3 p.Leu165fs (c.493_494del)?

CUL3 p.Leu165fs (c.493_494del) is associated with Inborn genetic diseases, pseudohypoaldosteronism type 2E, neurodevelopmental disorder with or without autism or seizures (ClinVar).

How common is CUL3 p.Leu165fs (c.493_494del) in the general population?

CUL3 p.Leu165fs (c.493_494del) is very rare (popmax 0.00167%, amr) (gnomAD).

CUL3 p.Leu165fs

c.493_494del · rs1553523940 · VCV503870

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 4 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -5.4	GERP -5.9
Overall
CADD	34.0	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 0.00167% Admixed American · 1/59,994 alleles

Overall 6.2e-05% 1/1,613,552 alleles · very rare exomes 0/1,461,346 · genomes 1/152,206 · 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: CUL3
Protein: p.Leu165fs
Coding: c.493_494del
MANE Select: NM_003590
dbSNP: rs1553523940
Type: Microsatellite
Location: chr2:224514657 (GRCh38)
Gene constraint: LOEUF 0.365 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.68 · 31 PDB
Residue 165: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pseudohypoaldosteronism type 2E neurodevelopmental disorder with or without autism or seizures

Similar variants

CUL3 p.Asp449_Ser450insTer Pathogenic/Likely pathogenic ★★ same condition
CUL3 p.Ile145fs Pathogenic ★★ same condition
CUL3 p.Ser517fs Pathogenic/Likely pathogenic ★★ same condition
CUL3 p.Glu79fs Pathogenic ★ same condition
CUL3 p.His543fs Likely pathogenic ★ same condition
CUL3 p.Met554fs Pathogenic ★ same condition
CUL3 p.Val129fs Likely pathogenic ★ same condition
CUL3 c.2176-9_2176-6del 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/cul3-p-leu165fs (accessed [today's date]).

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