# NM_001743.6(CALM2):c.57A>G (p.Leu19=)

https://sugi.bio/variant/calm2-p-leu19

## Summary

**CALM2 p.Leu19= (c.57A>G)** is classified **Likely benign** in CALM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-28). Very rare (popmax 0.000936%, nfe); Associated with long QT syndrome 1.

**At a glance:** Likely benign · review: Single submitter · rsID rs754538204 · 1 submitter · 1 linked condition · very rare (popmax 0.000936%, nfe)

## For patients & families {#patients}

This is a change in the CALM2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to long QT syndrome 1.

*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, Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CALM2 is a diagnostic-grade gene on 5 Genomics England panels |

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

- Prolonged QTc interval — Obligate (100%)
- Syncope — Frequent (79-30%)
- Sinus bradycardia — Frequent (79-30%)
- Abnormal T-wave — Frequent (79-30%)
- Seizure — Occasional (29-5%)
- Sudden cardiac death — Occasional (29-5%)
- Torsade de pointes — Occasional (29-5%)
- Ventricular arrhythmia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026140/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CALM2](https://sugi.bio/atlas/gene/CALM2/) |
| Protein change (HGVS p.) | p.Leu19= |
| Coding change (HGVS c.) | c.57A>G |
| MANE Select transcript | [NM_001743](https://www.ncbi.nlm.nih.gov/nuccore/NM_001743) |
| dbSNP | [rs754538204](https://www.ncbi.nlm.nih.gov/snp/rs754538204/) |
| Variant type | single nucleotide variant |
| Location | chr2:47162640-47162640 (GRCh38) |
| ClinVar | [VCV1132401](https://www.ncbi.nlm.nih.gov/clinvar/variation/1132401/) |

**All HGVS expressions:** `NC_000002.11:g.47389779T>C`, `NC_000002.12:g.47162640T>C`, `NG_042065.1:g.19297A>G`, `NM_001305624.1:c.201A>G`, `NM_001305625.2:c.-52A>G`, `NM_001305626.1:c.-52A>G`, `NM_001743.6:c.57A>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 (below), not from a missing predictor score.
- Conservation: phyloP 0.737, GERP -1.32, phastCons 1 — weakly conserved position
- CADD: **PHRED 9.371**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.31 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 **0.000936%** (nfe) · FAF95 0.000502% · FAF99 0.000367% · 11/1,175,054 in the highest group · 11/1,450,764 alleles overall — very rare (popmax 0.000936%, 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}

**CALM2** population constraint: LOEUF 0.262, pLI 0.99327, missense-Z 3.5543; 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 **19** lies in the ef-hand 1 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 85.82, 45% of residues very-high.

**21 experimental structure(s)** (PDB): [3O77](https://www.rcsb.org/structure/3O77), [3O78](https://www.rcsb.org/structure/3O78), [5COC](https://www.rcsb.org/structure/5COC), [6MUD](https://www.rcsb.org/structure/6MUD), [6PLM](https://www.rcsb.org/structure/6PLM), [6S5T](https://www.rcsb.org/structure/6S5T).

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

*Describes the biological roles of CALM2 (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:** CALM2's established molecular role includes calcium channel regulator activity. p.Leu19= falls in the ef-hand 1 domain. In Reactome, CALM2 is annotated in disease pathway(s) including **Enterobacterial factors antagonize host defense **.

**Disease mechanism (Reactome):** CALM2 loss or alteration is curated in [Enterobacterial factors antagonize host defense ](https://reactome.org/content/detail/R-HSA-9956593).

### Pathways affected {#pathways}

CALM2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Enterobacterial factors antagonize host defense ](https://reactome.org/content/detail/R-HSA-9956593) | curated |
| [CASP4 inflammasome assembly](https://reactome.org/content/detail/R-HSA-9948001) | curated |

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

**Molecular function:** calcium channel regulator activity, calcium ion binding, adenylate cyclase binding, adenylate cyclase activator activity, calcium channel inhibitor activity, protein kinase 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, substantia nigra development, regulation of cytokinesis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-10-28.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2020-10-28 |

## Associated conditions {#conditions}

[long QT syndrome 1](https://sugi.bio/atlas/disease/long-qt-syndrome-1/).

**Reported phenotype names (ClinVar):** Long QT syndrome 1.

## Similar variants {#similar}

Related CALM2 variant pages (same residue, condition, or type): [CALM2 p.Asn98Ser](/variant/calm2-p-asn98ser), [CALM2 p.Asp134Asn](/variant/calm2-p-asp134asn), [CALM2 p.Asp96Tyr](/variant/calm2-p-asp96tyr), [CALM2 p.Asp96Val](/variant/calm2-p-asp96val), [CALM2 c.285+5G>A](/variant/calm2-c-285-plus-5g-a), [CALM2 p.Ala58Pro](/variant/calm2-p-ala58pro), [CALM2 p.Arg107Cys](/variant/calm2-p-arg107cys), [CALM2 p.Arg91Cys](/variant/calm2-p-arg91cys).

### 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 1132401). 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.*