Is CUL3 p.Ser684= (c.2052C>T) pathogenic?

CUL3 p.Ser684= (c.2052C>T) is classified Benign/Likely benign in CUL3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Low-frequency (popmax 4.37%, afr); Associated with pseudohypoaldosteronism type 2E.

What condition is associated with CUL3 p.Ser684= (c.2052C>T)?

CUL3 p.Ser684= (c.2052C>T) is associated with pseudohypoaldosteronism type 2E, neurodevelopmental disorder with or without autism or seizures (ClinVar).

How common is CUL3 p.Ser684= (c.2052C>T) in the general population?

CUL3 p.Ser684= (c.2052C>T) is low-frequency (popmax 4.37%, afr) (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.Ser684=

c.2052C>T · rs61743301 · VCV334627

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.37%, afr)

Conditions

pseudohypoaldosteronism type 2E

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.8	GERP -3.9
Overall
CADD	2.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.37% African / African-American · 3,270/74,780 alleles

Filtering AF 4.25% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.2%

Overall 0.233% 3,757/1,611,226 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.37%	23
Remaining individualsnot grpmax-eligible	0.321%	312
Admixed American	0.317%	315
Middle Eastern	0.232%	432
South Asian	0.0122%	8,219
European (non-Finnish)	0.00619%	16,150

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.Ser684=
Coding: c.2052C>T
MANE Select: NM_003590
dbSNP: rs61743301
Type: single nucleotide variant
Location: chr2:224478323 (GRCh38)
Gene constraint: LOEUF 0.365 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.68 · 31 PDB
Residue 684: a UniProt-annotated variant site (in nedaus); the 'disordered' region

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

Disease context

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

Also linked: neurodevelopmental disorder with or without autism or seizures

For Pseudohypoaldosteronism type 2 (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

CUL3 c.1377+4A>G Likely pathogenic ★★ same condition
CUL3 c.883+1G>T Pathogenic ★★ same condition
CUL3 p.Arg128Cys Pathogenic/Likely pathogenic ★★ same condition
CUL3 p.Arg148Ter Pathogenic ★★ same condition
CUL3 p.Arg247Ter Pathogenic ★★ same condition
CUL3 p.Arg438Gly Pathogenic ★★ same condition
CUL3 p.Gln641Ter Pathogenic ★★ same condition
CUL3 p.Gly143Ter Likely 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-ser684 (accessed [today's date]).

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