# NM_003590.5(CUL3):c.1462A>C (p.Arg488=)

https://sugi.bio/variant/cul3-p-arg488

## Summary

**CUL3 p.Arg488= (c.1462A>C)** is classified **Uncertain significance** in CUL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Very rare (popmax 8.48e-05%, nfe); Associated with pseudohypoaldosteronism type 2E.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1692449966 · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the CUL3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to pseudohypoaldosteronism type 2E.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | CUL3 is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Pseudohypoaldosteronism type 2** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypertension — Very frequent (99-80%)
- Hyperkalemia — Very frequent (99-80%)
- Nausea and vomiting — Frequent (79-30%)
- Abnormality of the dentition — Occasional (29-5%)
- Abnormality of dental enamel — Occasional (29-5%)
- Muscle weakness — Occasional (29-5%)
- Growth delay — Occasional (29-5%)
- Periodic paralysis — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017373/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CUL3](https://sugi.bio/atlas/gene/CUL3/) |
| Protein change (HGVS p.) | p.Arg488= |
| Coding change (HGVS c.) | c.1462A>C |
| MANE Select transcript | [NM_003590](https://www.ncbi.nlm.nih.gov/nuccore/NM_003590) |
| dbSNP | [rs1692449966](https://www.ncbi.nlm.nih.gov/snp/rs1692449966/) |
| Variant type | single nucleotide variant |
| Location | chr2:224502988-224502988 (GRCh38) |
| ClinVar | [VCV895279](https://www.ncbi.nlm.nih.gov/clinvar/variation/895279/) |

**All HGVS expressions:** `NC_000002.11:g.225367705T>G`, `NC_000002.12:g.224502988T>G`, `NG_032169.1:g.87410A>C`, `NM_001257197.2:c.1264A>C`, `NM_001257198.2:c.1480A>C`, `NM_003590.5:c.1462A>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 4.218, GERP 1.77, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 12.82**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,636 in the highest group · 1/1,461,382 alleles overall — very rare (popmax 8.48e-05%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CUL3** population constraint: LOEUF 0.365, pLI 0.99999, missense-Z 5.156. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **pseudohypoaldosteronism type 2E** — Definitive (AD)
- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.68, 81% of residues very-high.

**31 experimental structure(s)** (PDB): [2MYL](https://www.rcsb.org/structure/2MYL), [2MYM](https://www.rcsb.org/structure/2MYM), [4AP2](https://www.rcsb.org/structure/4AP2), [4APF](https://www.rcsb.org/structure/4APF), [4EOZ](https://www.rcsb.org/structure/4EOZ), [4HXI](https://www.rcsb.org/structure/4HXI).

## What this gene does {#gene-function}

*Describes the biological roles of CUL3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CUL3's established molecular role includes Notch binding. In Reactome, CUL3 is annotated in disease pathway(s) including **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** CUL3 loss or alteration is curated in [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

CUL3 participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Degradation of DVL](https://reactome.org/content/detail/R-HSA-4641258) | curated |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | curated |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [RHOBTB1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013422) | curated |
| [RHOBTB2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013418) | curated |
| [RHOBTB3 ATPase cycle](https://reactome.org/content/detail/R-HSA-9706019) | curated |
| [Regulation of RAS by GAPs](https://reactome.org/content/detail/R-HSA-5658442) | curated |
| [SPOP-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929491) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** Notch binding, POZ domain binding, ubiquitin protein ligase binding, ubiquitin protein ligase activity, ubiquitin ligase complex scaffold activity.

**Biological process:** protein polyubiquitination, ubiquitin-dependent protein catabolic process, protein monoubiquitination, endoplasmic reticulum to Golgi vesicle-mediated transport, mitotic metaphase chromosome alignment, cell migration.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-12.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |

## Associated conditions {#conditions}

[pseudohypoaldosteronism type 2E](https://sugi.bio/atlas/disease/pseudohypoaldosteronism-type-2e/).

**Reported phenotype names (ClinVar):** Pseudohypoaldosteronism type 2E, Pseudohypoaldosteronism Type IIE.

## Similar variants {#similar}

Related CUL3 variant pages (same residue, condition, or type): [CUL3 c.1377+4A>G](/variant/cul3-c-1377-plus-4a-g), [CUL3 p.Arg247Ter](/variant/cul3-p-arg247ter), [CUL3 p.Arg438Gly](/variant/cul3-p-arg438gly), [CUL3 p.Gly143Ter](/variant/cul3-p-gly143ter), [CUL3 c.1377+6G>T](/variant/cul3-c-1377-plus-6g-t), [CUL3 c.-201C>G](/variant/cul3-c-minus-201c-g), [CUL3 p.Ala415Thr](/variant/cul3-p-ala415thr), [CUL3 p.Ala732Val](/variant/cul3-p-ala732val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 895279). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*