# NM_001128840.3(CACNA1D):c.6417C>T (p.Asp2139=)

https://sugi.bio/variant/cacna1d-p-asp2139

## Summary

**CACNA1D p.Asp2139= (c.6417C>T)** is classified **Conflicting classifications of pathogenicity** in CACNA1D (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-13). Rare (popmax 0.14%, afr).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs375811590 · 6 submitters · rare (popmax 0.14%, afr)

## For patients & families {#patients}

This is a change in the CACNA1D gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CACNA1D](https://sugi.bio/atlas/gene/CACNA1D/) |
| Protein change (HGVS p.) | p.Asp2139= |
| Coding change (HGVS c.) | c.6417C>T |
| MANE Select transcript | [NM_001128840](https://www.ncbi.nlm.nih.gov/nuccore/NM_001128840) |
| dbSNP | [rs375811590](https://www.ncbi.nlm.nih.gov/snp/rs375811590/) |
| Variant type | single nucleotide variant |
| Location | chr3:53811337-53811337 (GRCh38) |
| ClinVar | [VCV504771](https://www.ncbi.nlm.nih.gov/clinvar/variation/504771/) |

**All HGVS expressions:** `NC_000003.11:g.53845364C>T`, `NC_000003.12:g.53811337C>T`, `NG_032999.1:g.321289C>T`, `NM_000720.4:c.6477C>T`, `NM_001128839.3:c.6345C>T`, `NM_001128840.3:c.6417C>T`

## 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 -8.062, GERP -4.14 — fast-evolving / accelerated position
- CADD: **PHRED 1.558**. 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 **0.14%** (afr) · FAF95 0.119% · FAF99 0.11% · 105/74,800 in the highest group · 134/1,605,270 alleles overall — rare (popmax 0.14%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.14% | 712 |
| Middle Eastern | 0.0334% | 2,990 |
| Remaining individuals (not grpmax-eligible) | 0.0113% | 8,872 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00342% | 29,266 |
| Admixed American | 0.00168% | 59,660 |
| European (non-Finnish) | 0.00153% | 65,218 |

*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}

**CACNA1D** population constraint: LOEUF 0.253, pLI 1, missense-Z 6.624. *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):

- **sinoatrial node dysfunction and deafness** — Moderate (AR)
- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **2139** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 64.60, 12% of residues very-high.

**6 experimental structure(s)** (PDB): [3LV3](https://www.rcsb.org/structure/3LV3), [7UHF](https://www.rcsb.org/structure/7UHF), [7UHG](https://www.rcsb.org/structure/7UHG), [8E59](https://www.rcsb.org/structure/8E59), [8E5A](https://www.rcsb.org/structure/8E5A), [8E5B](https://www.rcsb.org/structure/8E5B).

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

*Describes the biological roles of CACNA1D (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:** CACNA1D's established molecular role includes voltage-gated calcium channel activity. p.Asp2139= falls in the disordered region.


### Pathways affected {#pathways}

CACNA1D participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Adrenaline,noradrenaline inhibits insulin secretion](https://reactome.org/content/detail/R-HSA-400042) | 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, calcium channel activity, alpha-actinin binding, voltage-gated calcium channel activity involved SA node cell action potential.

**Biological process:** calcium ion transport, sensory perception of sound, positive regulation of calcium ion transport, calcium ion import, cardiac muscle cell action potential involved in contraction, membrane depolarization during SA node cell action potential.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-13.

**Submitter consensus:** conflicting (5 Likely benign, 1 Uncertain significance).

**Submission history:** 6 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2016-08-31 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-07-28 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-07-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-13 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-06-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-25 |

**Reported phenotype names (ClinVar):** not provided, not specified, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related CACNA1D variant pages (same residue, condition, or type): [CACNA1D p.Asp2139Asn](/variant/cacna1d-p-asp2139asn), [CACNA1D p.Ser652Leu](/variant/cacna1d-p-ser652leu), [CACNA1D c.1892+3A>G](/variant/cacna1d-c-1892-plus-3a-g), [CACNA1D c.2406+3A>G](/variant/cacna1d-c-2406-plus-3a-g), [CACNA1D c.2474-1G>A](/variant/cacna1d-c-2474-minus-1g-a), [CACNA1D c.2474-2A>C](/variant/cacna1d-c-2474-minus-2a-c), [CACNA1D c.2751+2T>C](/variant/cacna1d-c-2751-plus-2t-c), [CACNA1D c.3314+1G>A](/variant/cacna1d-c-3314-plus-1g-a).

### 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 504771). 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.*