# NM_006888.6(CALM1):c.69T>C (p.Asp23=)

https://sugi.bio/variant/calm1-p-asp23

## Summary

**CALM1 p.Asp23= (c.69T>C)** is classified **Likely benign** in CALM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-13). Rare (popmax 0.127%, afr); Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs144339242 · 2 submitters · 3 linked conditions · rare (popmax 0.127%, afr)

## For patients & families {#patients}

This is a change in the CALM1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Cardiovascular phenotype.

*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 | [CALM1](https://sugi.bio/atlas/gene/CALM1/) |
| Protein change (HGVS p.) | p.Asp23= |
| Coding change (HGVS c.) | c.69T>C |
| MANE Select transcript | [NM_006888](https://www.ncbi.nlm.nih.gov/nuccore/NM_006888) |
| dbSNP | [rs144339242](https://www.ncbi.nlm.nih.gov/snp/rs144339242/) |
| Variant type | single nucleotide variant |
| Location | chr14:90401293-90401293 (GRCh38) |
| ClinVar | [VCV475382](https://www.ncbi.nlm.nih.gov/clinvar/variation/475382/) |

**All HGVS expressions:** `NC_000014.8:g.90867637T>C`, `NC_000014.9:g.90401293T>C`, `NG_013338.1:g.9311T>C`, `NM_001363669.2:c.-40T>C`, `NM_001363670.2:c.72T>C`, `NM_006888.6:c.69T>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 0.722, GERP 0.787, phastCons 1 — weakly conserved position
- CADD: **PHRED 8.986**. 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 **0.127%** (afr) · FAF95 0.106% · FAF99 0.0982% · 95/75,054 in the highest group · 113/1,614,112 alleles overall — rare (popmax 0.127%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.127% | 790 |
| Middle Eastern | 0.033% | 3,031 |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,250 |
| Admixed American | 0.00666% | 15,008 |
| European (non-Finnish) | 0.00017% | 589,960 |

*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}

**CALM1** population constraint: LOEUF 0.276, pLI 0.991, missense-Z 3.5866; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *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):

- **catecholaminergic polymorphic ventricular tachycardia** — Moderate (AD)
- **long QT syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **23** lies in the ef-hand 1 domain; a β-strand; a binding site.

AlphaFold model confidence (whole protein): pLDDT 85.22, 43% of residues very-high.

**351 experimental structure(s)** (PDB): [10NK](https://www.rcsb.org/structure/10NK), [10NL](https://www.rcsb.org/structure/10NL), [12DK](https://www.rcsb.org/structure/12DK), [1CDL](https://www.rcsb.org/structure/1CDL), [1CLL](https://www.rcsb.org/structure/1CLL), [1CTR](https://www.rcsb.org/structure/1CTR) — incl. mutant structure 1XFU.

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

*Describes the biological roles of CALM1 (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:** CALM1's established molecular role includes calcium channel regulator activity. p.Asp23= falls in the ef-hand 1 domain. In Reactome, CALM1 is annotated in disease pathway(s) including **Enterobacterial factors antagonize host defense **, **Paradoxical activation of RAF signaling by kinase inactive BRAF**.

**Disease mechanism (Reactome):** CALM1 loss or alteration is curated in [Enterobacterial factors antagonize host defense ](https://reactome.org/content/detail/R-HSA-9956593), [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952).

### Pathways affected {#pathways}

CALM1 participates in **56 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Enterobacterial factors antagonize host defense ](https://reactome.org/content/detail/R-HSA-9956593) | curated |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| ⚕ [Uptake and function of anthrax toxins](https://reactome.org/content/detail/R-HSA-5210891) | curated |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | electronic |
| ⚕ [Loss of phosphorylation of MECP2 at T308](https://reactome.org/content/detail/R-HSA-9022535) | electronic |
| [Activation of Ca-permeable Kainate Receptor](https://reactome.org/content/detail/R-HSA-451308) | curated |
| [CASP4 inflammasome assembly](https://reactome.org/content/detail/R-HSA-9948001) | curated |
| [Ca2+ pathway](https://reactome.org/content/detail/R-HSA-4086398) | curated |
| [Calmodulin induced events](https://reactome.org/content/detail/R-HSA-111933) | curated |
| [Cam-PDE 1 activation](https://reactome.org/content/detail/R-HSA-111957) | curated |
| [Extra-nuclear estrogen signaling](https://reactome.org/content/detail/R-HSA-9009391) | curated |
| [Ion homeostasis](https://reactome.org/content/detail/R-HSA-5578775) | curated |
| [Ion transport by P-type ATPases](https://reactome.org/content/detail/R-HSA-936837) | curated |
| [PKA activation](https://reactome.org/content/detail/R-HSA-163615) | curated |
| [Phase 0 - rapid depolarisation](https://reactome.org/content/detail/R-HSA-5576892) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Protein methylation](https://reactome.org/content/detail/R-HSA-8876725) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RAS processing](https://reactome.org/content/detail/R-HSA-9648002) | curated |
| [RHO GTPases activate IQGAPs](https://reactome.org/content/detail/R-HSA-5626467) | curated |
| [Reduction of cytosolic Ca++ levels](https://reactome.org/content/detail/R-HSA-418359) | curated |
| [Sodium/Calcium exchangers](https://reactome.org/content/detail/R-HSA-425561) | curated |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |
| [Synthesis of IP3 and IP4 in the cytosol](https://reactome.org/content/detail/R-HSA-1855204) | curated |
| [Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation](https://reactome.org/content/detail/R-HSA-1474151) | curated |
| [Unblocking of NMDA receptors, glutamate binding and activation](https://reactome.org/content/detail/R-HSA-438066) | curated |
| [VEGFR2 mediated vascular permeability](https://reactome.org/content/detail/R-HSA-5218920) | curated |
| [eNOS activation](https://reactome.org/content/detail/R-HSA-203615) | curated |
| [Activation of AMPK downstream of NMDARs](https://reactome.org/content/detail/R-HSA-9619483) | electronic |
| [Activation of RAC1 downstream of NMDARs](https://reactome.org/content/detail/R-HSA-9619229) | electronic |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |
| [CLEC7A (Dectin-1) induces NFAT activation](https://reactome.org/content/detail/R-HSA-5607763) | electronic |
| [CREB1 phosphorylation through the activation of Adenylate Cyclase](https://reactome.org/content/detail/R-HSA-442720) | electronic |
| [CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde](https://reactome.org/content/detail/R-HSA-442729) | electronic |
| [CaM pathway](https://reactome.org/content/detail/R-HSA-111997) | electronic |
| [CaMK IV-mediated phosphorylation of CREB](https://reactome.org/content/detail/R-HSA-111932) | electronic |
| [Calcineurin activates NFAT](https://reactome.org/content/detail/R-HSA-2025928) | electronic |
| [DARPP-32 events](https://reactome.org/content/detail/R-HSA-180024) | electronic |
| [FCERI mediated Ca+2 mobilization](https://reactome.org/content/detail/R-HSA-2871809) | electronic |
| [Glycogen breakdown (glycogenolysis)](https://reactome.org/content/detail/R-HSA-70221) | electronic |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | electronic |
| [Inactivation, recovery and regulation of the phototransduction cascade](https://reactome.org/content/detail/R-HSA-2514859) | electronic |
| [Long-term potentiation](https://reactome.org/content/detail/R-HSA-9620244) | electronic |
| [Negative regulation of NMDA receptor-mediated neuronal transmission](https://reactome.org/content/detail/R-HSA-9617324) | electronic |
| [RHO GTPases activate PAKs](https://reactome.org/content/detail/R-HSA-5627123) | electronic |
| [Ras activation upon Ca2+ influx through NMDA receptor](https://reactome.org/content/detail/R-HSA-442982) | electronic |
| [Regulation of MECP2 expression and activity](https://reactome.org/content/detail/R-HSA-9022692) | electronic |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | electronic |
| [Transcriptional activation of mitochondrial biogenesis](https://reactome.org/content/detail/R-HSA-2151201) | electronic |
| [Translocation of SLC2A4 (GLUT4) to the plasma membrane](https://reactome.org/content/detail/R-HSA-1445148) | electronic |
| [VEGFR2 mediated cell proliferation](https://reactome.org/content/detail/R-HSA-5218921) | electronic |

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

**Molecular function:** calcium channel regulator activity, calcium ion binding, adenylate cyclase activator activity, calcium channel inhibitor activity, protein kinase binding, titin binding.

**Biological process:** regulation of heart rate, detection of calcium ion, regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum, regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion, autophagosome membrane docking, substantia nigra development.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-13.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2017–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2017-07-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-13 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [catecholaminergic polymorphic ventricular tachycardia 4](https://sugi.bio/atlas/disease/catecholaminergic-polymorphic-ventricular-tachycardia-4/), [long QT syndrome 14](https://sugi.bio/atlas/disease/long-qt-syndrome-14/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Catecholaminergic polymorphic ventricular tachycardia 4, Long QT syndrome 14, CALM1-Related Catecholaminergic Polymorphic Ventricular Tachycardia.

## Similar variants {#similar}

Related CALM1 variant pages (same residue, condition, or type): [CALM1 p.Asp23Tyr](/variant/calm1-p-asp23tyr), [CALM1 p.Asn98Ser](/variant/calm1-p-asn98ser), [CALM1 p.Asp130Gly](/variant/calm1-p-asp130gly), [CALM1 c.4-3T>C](/variant/calm1-c-4-minus-3t-c), [CALM1 p.Arg87His](/variant/calm1-p-arg87his), [CALM1 p.Glu120Lys](/variant/calm1-p-glu120lys), [CALM1 c.178+18A>G](/variant/calm1-c-178-plus-18a-g), [CALM1 c.179-4C>T](/variant/calm1-c-179-minus-4c-t).

### 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 475382). 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.*