# NM_001743.6(CALM2):c.130C>T (p.Pro44Ser)

https://sugi.bio/variant/calm2-p-pro44ser

## Summary

**CALM2 p.Pro44Ser (c.130C>T)** is classified **Uncertain significance** in CALM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-01). Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2465709290 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CALM2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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 | [CALM2](https://sugi.bio/atlas/gene/CALM2/) |
| Protein change (HGVS p.) | p.Pro44Ser |
| Coding change (HGVS c.) | c.130C>T |
| MANE Select transcript | [NM_001743](https://www.ncbi.nlm.nih.gov/nuccore/NM_001743) |
| dbSNP | [rs2465709290](https://www.ncbi.nlm.nih.gov/snp/rs2465709290/) |
| Variant type | single nucleotide variant |
| Location | chr2:47162567-47162567 (GRCh38) |
| ClinVar | [VCV1769618](https://www.ncbi.nlm.nih.gov/clinvar/variation/1769618/) |

**All HGVS expressions:** `NC_000002.11:g.47389706G>A`, `NC_000002.12:g.47162567G>A`, `NG_042065.1:g.19370C>T`, `NM_001305624.1:c.274C>T`, `NM_001305625.2:c.22C>T`, `NM_001305626.1:c.22C>T`, `NM_001743.6:c.130C>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 10.006, GERP 2.21, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 26.9**. 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 0.21** across the covering region of the MANE Select transcript (47,160,779–47,176,443), spanning 15,664 bp — the region is depleted of missense variation. Chi-square p 6.7e-26. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **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}

**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 **44** lies in the ef-hand 2 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.Pro44Ser falls in the ef-hand 2 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-08-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-08-01 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype.

## Similar variants {#similar}

Related CALM2 variant pages (same residue, condition, or type): [CALM2 p.Pro44Arg](/variant/calm2-p-pro44arg), [CALM2 p.Asn98Ser](/variant/calm2-p-asn98ser), [CALM2 c.-2G>C](/variant/calm2-c-minus-2g-c), [CALM2 c.-4C>T](/variant/calm2-c-minus-4c-t), [CALM2 p.Arg107Cys](/variant/calm2-p-arg107cys), [CALM2 p.Glu140=](/variant/calm2-p-glu140), [CALM2 p.Val36Ile](/variant/calm2-p-val36ile), [CALM2 p.Asp81=](/variant/calm2-p-asp81).

### 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 1769618). 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.*