# NM_201596.3(CACNB2):c.1532G>C (p.Arg511Pro)

https://sugi.bio/variant/cacnb2-p-arg511pro

## Summary

**CACNB2 p.Arg511Pro (c.1532G>C)** is classified **Uncertain significance** in CACNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-13). AlphaMissense: likely benign (0.1026); Very rare (popmax 8.47e-05%, nfe); Associated with Brugada syndrome 4.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CACNB2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Brugada syndrome 4.

*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, Not applicable |
| Age of onset (of this condition) | Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |

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

- Syncope — Frequent (79-30%)
- Cardiac arrest — Frequent (79-30%)
- Right bundle branch block — Frequent (79-30%)
- ST segment elevation — Frequent (79-30%)
- Tachycardia — Occasional (29-5%)
- Ventricular fibrillation — Occasional (29-5%)
- Paroxysmal ventricular tachycardia — Occasional (29-5%)
- Supraventricular tachycardia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010362/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CACNB2](https://sugi.bio/atlas/gene/CACNB2/) |
| Protein change (HGVS p.) | p.Arg511Pro |
| Coding change (HGVS c.) | c.1532G>C |
| MANE Select transcript | [NM_201596](https://www.ncbi.nlm.nih.gov/nuccore/NM_201596) |
| Variant type | single nucleotide variant |
| Location | chr10:18539273-18539273 (GRCh38) |
| ClinVar | [VCV4806042](https://www.ncbi.nlm.nih.gov/clinvar/variation/4806042/) |

**All HGVS expressions:** `LRG_381:g.403597G>C`, `LRG_381t1:c.1532G>C`, `LRG_381t2:c.1370G>C`, `NC_000010.10:g.18828202G>C`, `NC_000010.11:g.18539273G>C`, `NG_016195.1:g.403597G>C`, `NM_000724.4:c.1367G>C`, `NM_001167945.2:c.1334G>C`, `NM_001330060.2:c.1253G>C`, `NM_001410882.1:c.1274G>C`, `NM_201570.3:c.1388G>C`, `NM_201571.4:c.1448G>C`, `NM_201572.4:c.1376G>C`, `NM_201590.3:c.1370G>C`, `NM_201593.3:c.1418G>C`, `NM_201596.3:c.1532G>C`, `NM_201597.3:c.1460G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1026)
- REVEL 0.284 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.138 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.837, GERP 1.75, phastCons 0.998 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.3**. 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.*
- Regional missense constraint: **o/e 1.10** across the covering region of the MANE Select transcript (18,140,737–18,539,721), spanning 398,984 bp. Chi-square p 0.0029. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.43 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,944 in the highest group · 1/1,461,838 alleles overall — very rare (popmax 8.47e-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}

**CACNB2** population constraint: LOEUF 0.77, pLI 9.0033e-06, missense-Z -0.71303. *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):

- **cardiogenetic disease** — Disputed (AD)

## Protein context {#protein}

Residue **511** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 65.78, 38% of residues very-high.

**3 experimental structure(s)** (PDB): [8HLP](https://www.rcsb.org/structure/8HLP), [8HMA](https://www.rcsb.org/structure/8HMA), [8HMB](https://www.rcsb.org/structure/8HMB).

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

*Describes the biological roles of CACNB2 (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:** CACNB2's established molecular role includes voltage-gated calcium channel activity. p.Arg511Pro falls in the disordered region.


### Pathways affected {#pathways}

CACNB2 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Phase 0 - rapid depolarisation](https://reactome.org/content/detail/R-HSA-5576892) | curated |
| [Phase 2 - plateau phase](https://reactome.org/content/detail/R-HSA-5576893) | curated |
| [Presynaptic depolarization and calcium channel opening](https://reactome.org/content/detail/R-HSA-112308) | curated |
| [Adrenaline,noradrenaline inhibits insulin secretion](https://reactome.org/content/detail/R-HSA-400042) | electronic |
| [Mechanical load activates signaling by PIEZO1 and integrins in osteocytes](https://reactome.org/content/detail/R-HSA-9856532) | electronic |
| [NCAM1 interactions](https://reactome.org/content/detail/R-HSA-419037) | electronic |
| [Regulation of insulin secretion](https://reactome.org/content/detail/R-HSA-422356) | electronic |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |

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

**Molecular function:** voltage-gated calcium channel activity.

**Biological process:** positive regulation of calcium ion transport, calcium ion import, membrane depolarization during AV node cell action potential, regulation of heart rate by cardiac conduction, membrane depolarization during atrial cardiac muscle cell action potential.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-13 |

## Associated conditions {#conditions}

[Brugada syndrome 4](https://sugi.bio/atlas/disease/brugada-syndrome-4/).

**Reported phenotype names (ClinVar):** Brugada syndrome 4.

## Similar variants {#similar}

Related CACNB2 variant pages (same residue, condition, or type): [CACNB2 p.Arg511Cys](/variant/cacnb2-p-arg511cys), [CACNB2 p.Arg511His](/variant/cacnb2-p-arg511his), [CACNB2 p.Arg511Ser](/variant/cacnb2-p-arg511ser), [CACNB2 c.1206+5G>A](/variant/cacnb2-c-1206-plus-5g-a), [CACNB2 c.1303-3C>T](/variant/cacnb2-c-1303-minus-3c-t), [CACNB2 c.1488+6G>A](/variant/cacnb2-c-1488-plus-6g-a), [CACNB2 p.Ala105Thr](/variant/cacnb2-p-ala105thr), [CACNB2 p.Ala118Val](/variant/cacnb2-p-ala118val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 4806042). 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.*