# NM_001127222.2(CACNA1A):c.4988G>A (p.Arg1663Gln)

https://sugi.bio/variant/cacna1a-p-arg1663gln

## Summary

**CACNA1A p.Arg1663Gln (c.4988G>A)** is classified **Pathogenic/Likely pathogenic** in CACNA1A (ClinVar, Multiple submitters, 20 submitters; last evaluated 2025-11-14). AlphaMissense: likely pathogenic (0.9898); Absent from gnomAD v4.1; Associated with spinocerebellar ataxia type 6.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs121908247 · 20 submitters · 5 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CACNA1A gene that is considered likely disease-causing, submitted by 20 submitters, and is linked to spinocerebellar ataxia type 6.

*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 |
| Age of onset (of this condition) | Adolescent, Adult, Elderly |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Clinical trials | 12 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CACNA1A is a diagnostic-grade gene on 20 Genomics England panels |

**Commonly reported features of Spinocerebellar ataxia type 6** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Nystagmus — Very frequent (99-80%)
- Gait ataxia — Very frequent (99-80%)
- Progressive cerebellar ataxia — Very frequent (99-80%)
- Intention tremor — Very frequent (99-80%)
- Postural instability — Very frequent (99-80%)
- Incoordination — Very frequent (99-80%)
- Unsteady gait — Very frequent (99-80%)
- Gaze-evoked horizontal nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010351/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CACNA1A](https://sugi.bio/atlas/gene/CACNA1A/) |
| Protein change (HGVS p.) | p.Arg1663Gln |
| Coding change (HGVS c.) | c.4988G>A |
| MANE Select transcript | [NM_001127222](https://www.ncbi.nlm.nih.gov/nuccore/NM_001127222) |
| dbSNP | [rs121908247](https://www.ncbi.nlm.nih.gov/snp/rs121908247/) |
| Variant type | single nucleotide variant |
| Location | chr19:13235693-13235693 (GRCh38) |
| ClinVar | [VCV68432](https://www.ncbi.nlm.nih.gov/clinvar/variation/68432/) |

**All HGVS expressions:** `LRG_7:g.275768G>A`, `LRG_7t1:c.4991G>A`, `NC_000019.10:g.13235693C>T`, `NC_000019.9:g.13346507C>T`, `NG_011569.1:g.275768G>A`, `NM_000068.4:c.5006G>A`, `NM_001127221.2:c.4991G>A`, `NM_001127222.2:c.4988G>A`, `NM_001174080.2:c.4997G>A`, `NM_023035.3:c.5006G>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9898) — concordant with the pathogenic call
- REVEL 0.967 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.325 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.49) — consistent with the pathogenic call
- Conservation: phyloP 7.645, GERP 2.65, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 35.0**. 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 0.34** across the covering region of the MANE Select transcript (13,235,013–13,255,133), spanning 20,120 bp — the region is depleted of missense variation. Chi-square p 1.8e-20. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.49**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.49**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CACNA1A** population constraint: LOEUF 0.331, pLI 1, missense-Z 3.9533; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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 movement disorder with or without neurodevelopmental features** — Definitive (AR)

## Protein context {#protein}

Residue **1663** lies in a UniProt-annotated variant site (in ea2 and sca6); a UniProt-annotated variant site (in sca6; pathogenic; also found in patients with global developmental delay and congenital ataxia; loss of function observed in the drosophila homolog); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 58.34, 5% of residues very-high.

**4 experimental structure(s)** (PDB): [3BXK](https://www.rcsb.org/structure/3BXK), [8X90](https://www.rcsb.org/structure/8X90), [8X91](https://www.rcsb.org/structure/8X91), [8X93](https://www.rcsb.org/structure/8X93).

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

*Describes the biological roles of CACNA1A (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:** CACNA1A's established molecular role includes voltage-gated calcium channel activity.


### Pathways affected {#pathways}

CACNA1A participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Presynaptic depolarization and calcium channel opening](https://reactome.org/content/detail/R-HSA-112308) | curated |
| [Regulation of insulin secretion](https://reactome.org/content/detail/R-HSA-422356) | curated |

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

**Molecular function:** voltage-gated calcium channel activity, high voltage-gated calcium channel activity, syntaxin binding.

**Biological process:** positive regulation of cytosolic calcium ion concentration, modulation of chemical synaptic transmission, calcium ion transmembrane transport, response to amyloid-beta, cellular response to amyloid-beta.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-14.

**Submitter consensus:** conflicting (14 Pathogenic, 4 Likely pathogenic, 2 not provided, 1 Uncertain significance).

**Submission history:** 21 submissions (2014–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mendelics | Pathogenic | no assertion criteria provided | clinical testing | 2014-11-30 |
| Athena Diagnostics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-06-16 |
| Baylor Genetics | Uncertain significance | flagged submission | clinical testing | 2017-09-01 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-12 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-12 |
| UniProtKB/Swiss-Prot | not provided | no classification provided | not provided |  |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Pathogenic | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely pathogenic | no assertion criteria provided | clinical testing |  |
| Pediatric Department, Xiangya Hospital, Central South University | Pathogenic | criteria provided, single submitter | clinical testing | 2021-01-07 |
| GenomeConnect - Brain Gene Registry | not provided | no classification provided | phenotyping only |  |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-07 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-14 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Likely pathogenic | criteria provided, single submitter | clinical testing | 2014-05-20 |
| Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea | Pathogenic | no assertion criteria provided | research | 2019-02-11 |
| Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Pathogenic | criteria provided, single submitter | clinical testing |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-14 |
| Solve-RD Consortium | Likely pathogenic | no assertion criteria provided | provider interpretation | 2022-06-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-19 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-02 |

## Associated conditions {#conditions}

[spinocerebellar ataxia type 6](https://sugi.bio/atlas/disease/spinocerebellar-ataxia-type-6/), [episodic ataxia type 2](https://sugi.bio/atlas/disease/episodic-ataxia-type-2/), [developmental and epileptic encephalopathy, 42](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-42/), [mega-cisterna magna](https://sugi.bio/atlas/disease/mega-cisterna-magna/), [migraine, familial hemiplegic, 1](https://sugi.bio/atlas/disease/migraine-familial-hemiplegic-1/).

**Reported phenotype names (ClinVar):** Spinocerebellar ataxia type 6, not provided, Enlarged cisterna magna, Global developmental delay, Developmental and epileptic encephalopathy, 42, Episodic ataxia type 2, Ataxia _ Neurologic (child onset), Non-progressive congenital cerebellar ataxia, Chronic and progressive ataxia, Neurodevelopmental delay.

## Same-residue context {#hotspot}

Residue **1663** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CACNA1A p.Arg1663Ter](/variant/cacna1a-p-arg1663ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CACNA1A variant pages (same residue, condition, or type): [CACNA1A p.Arg1663Ter](/variant/cacna1a-p-arg1663ter), [CACNA1A c.1082+1G>A](/variant/cacna1a-c-1082-plus-1g-a), [CACNA1A c.1198+1G>A](/variant/cacna1a-c-1198-plus-1g-a), [CACNA1A c.2105-2A>G](/variant/cacna1a-c-2105-minus-2a-g), [CACNA1A c.3692+1G>A](/variant/cacna1a-c-3692-plus-1g-a), [CACNA1A c.3822+1G>A](/variant/cacna1a-c-3822-plus-1g-a), [CACNA1A c.3989+1G>A](/variant/cacna1a-c-3989-plus-1g-a), [CACNA1A c.3989+1G>T](/variant/cacna1a-c-3989-plus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 68432). 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.*