# NM_006030.4(CACNA2D2):c.2046A>G (p.Arg682=)

https://sugi.bio/variant/cacna2d2-p-arg682

## Summary

**CACNA2D2 p.Arg682= (c.2046A>G)** is classified **Uncertain significance** in CACNA2D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-21). Very rare (popmax 8.56e-05%, nfe); Associated with early-infantile DEE.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1240659762 · 1 submitter · 1 linked condition · very rare (popmax 8.56e-05%, nfe)

## For patients & families {#patients}

This is a change in the CACNA2D2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to early-infantile DEE.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027299/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CACNA2D2](https://sugi.bio/atlas/gene/CACNA2D2/) |
| Protein change (HGVS p.) | p.Arg682= |
| Coding change (HGVS c.) | c.2046A>G |
| MANE Select transcript | [NM_006030](https://www.ncbi.nlm.nih.gov/nuccore/NM_006030) |
| dbSNP | [rs1240659762](https://www.ncbi.nlm.nih.gov/snp/rs1240659762/) |
| Variant type | single nucleotide variant |
| Location | chr3:50368235-50368235 (GRCh38) |
| ClinVar | [VCV1008434](https://www.ncbi.nlm.nih.gov/clinvar/variation/1008434/) |

**All HGVS expressions:** `NC_000003.11:g.50405666T>C`, `NC_000003.12:g.50368235T>C`, `NG_034070.1:g.141010A>G`, `NM_001005505.3:c.2046A>G`, `NM_001174051.3:c.2067A>G`, `NM_001291101.1:c.1839A>G`, `NM_006030.4:c.2046A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.865, GERP 2.27, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.98**. 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 deltas (raw): acceptor loss **0.22**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **8.56e-05%** (nfe) · 1/1,167,970 in the highest group · 1/152,086 alleles overall — very rare (popmax 8.56e-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}

**CACNA2D2** population constraint: LOEUF 0.396, pLI 1, missense-Z 3.1353. *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):

- **complex neurodevelopmental disorder** — Moderate (AR)

## Protein context {#protein}

Residue **682** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 81.48, 47% of residues very-high.

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

*Describes the biological roles of CACNA2D2 (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.*


### Pathways affected {#pathways}

CACNA2D2 participates in **6 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 |
| [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 |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-06-21.

**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 | 2020-06-21 |

## Associated conditions {#conditions}

[early-infantile DEE](https://sugi.bio/atlas/disease/early-infantile-dee/).

**Reported phenotype names (ClinVar):** Early-infantile DEE, Early infantile epileptic encephalopathy with suppression bursts, Early infantile epileptic encephalopathy, Ohtahara syndrome.

## Similar variants {#similar}

Related CACNA2D2 variant pages (same residue, condition, or type): [CACNA2D2 c.2234+1G>A](/variant/cacna2d2-c-2234-plus-1g-a), [CACNA2D2 p.Gln519Ter](/variant/cacna2d2-p-gln519ter), [CACNA2D2 c.1907+3A>C](/variant/cacna2d2-c-1907-plus-3a-c), [CACNA2D2 c.785-3C>T](/variant/cacna2d2-c-785-minus-3c-t), [CACNA2D2 p.Ala1096Thr](/variant/cacna2d2-p-ala1096thr), [CACNA2D2 p.Ala253Thr](/variant/cacna2d2-p-ala253thr), [CACNA2D2 p.Arg188Ser](/variant/cacna2d2-p-arg188ser), [CACNA2D2 p.Arg422Cys](/variant/cacna2d2-p-arg422cys).

### 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 1008434). 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.*