Is CUL3 p.Ala327Val (c.980C>T) pathogenic?

CUL3 p.Ala327Val (c.980C>T) is classified Uncertain significance in CUL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-18). AlphaMissense: likely benign (0.1563); Absent from gnomAD v4.1; Associated with pseudohypoaldosteronism type 2E.

What condition is associated with CUL3 p.Ala327Val (c.980C>T)?

CUL3 p.Ala327Val (c.980C>T) is associated with pseudohypoaldosteronism type 2E, neurodevelopmental disorder with or without autism or seizures (ClinVar).

How common is CUL3 p.Ala327Val (c.980C>T) in the general population?

CUL3 p.Ala327Val (c.980C>T) 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.

What do computational predictors say about CUL3 p.Ala327Val (c.980C>T)?

AlphaMissense predicts likely benign (score 0.1563) — an in-silico prediction, not a clinical call.

CUL3 p.Ala327Val

c.980C>T · VCV3585715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1563 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pseudohypoaldosteronism type 2E

Computational evidence

Protein change
AlphaMissense	0.1563	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 76 kb · p 5e-41 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Ala327Val
Coding: c.980C>T
MANE Select: NM_003590
Type: single nucleotide variant
Location: chr2:224506907 (GRCh38)
Gene constraint: LOEUF 0.365 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.68 · 31 PDB
Residue 327: an α-helix

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-ala327val (accessed [today's date]).

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