# NM_005173.4(ATP2A3):c.1155G>C (p.Ser385=)

https://sugi.bio/variant/atp2a3-p-ser385

## Summary

**ATP2A3 p.Ser385= (c.1155G>C)** is classified **Likely benign** in ATP2A3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-12). Ultra-rare (popmax 0.0687%, eas); Associated with ATP2A3-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs1032107053 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0687%, eas)

## For patients & families {#patients}

This is a change in the ATP2A3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to ATP2A3-related disorder.

*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 | [ATP2A3](https://sugi.bio/atlas/gene/ATP2A3/) |
| Protein change (HGVS p.) | p.Ser385= |
| Coding change (HGVS c.) | c.1155G>C |
| MANE Select transcript | [NM_005173](https://www.ncbi.nlm.nih.gov/nuccore/NM_005173) |
| dbSNP | [rs1032107053](https://www.ncbi.nlm.nih.gov/snp/rs1032107053/) |
| Variant type | single nucleotide variant |
| Location | chr17:3945089-3945089 (GRCh38) |
| ClinVar | [VCV3050071](https://www.ncbi.nlm.nih.gov/clinvar/variation/3050071/) |

**All HGVS expressions:** `NC_000017.10:g.3848383C>G`, `NC_000017.11:g.3945089C>G`, `NG_029041.1:g.24354G>C`, `NG_194425.1:g.352C>G`, `NM_005173.4:c.1155G>C`, `NM_174953.3:c.1155G>C`, `NM_174954.3:c.1155G>C`, `NM_174955.3:c.1155G>C`, `NM_174956.3:c.1155G>C`, `NM_174957.3:c.1155G>C`, `NM_174958.3:c.1155G>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 -20, GERP -3.44 — fast-evolving / accelerated position
- CADD: **PHRED 2.864**. 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 (C>T, Δ0.90 donor 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 **0.0687%** (eas) · FAF95 0.0488% · FAF99 0.0421% · 28/40,760 in the highest group · 66/1,547,650 alleles overall — ultra-rare (popmax 0.0687%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0687% | 1,456 |
| Remaining individuals (not grpmax-eligible) | 0.0585% | 1,711 |
| Admixed American | 0.00393% | 25,454 |
| South Asian | 0.00119% | 83,998 |

*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}

**ATP2A3** population constraint: LOEUF 0.759, pLI 5.7777e-12, missense-Z 2.0809. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **385** lies in the 'interaction with phospholamban 1' region.

AlphaFold model confidence (whole protein): pLDDT 86.75, 45% of residues very-high.

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

*Describes the biological roles of ATP2A3 (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:** ATP2A3's established molecular role includes calcium channel regulator activity. p.Ser385= falls in the interaction with phospholamban 1 region.


### Pathways affected {#pathways}

ATP2A3 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |
| [Reduction of cytosolic Ca++ levels](https://reactome.org/content/detail/R-HSA-418359) | curated |
| [Pre-NOTCH Processing in Golgi](https://reactome.org/content/detail/R-HSA-1912420) | electronic |

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

**Molecular function:** calcium channel regulator activity, P-type calcium transporter activity, cysteine-type endopeptidase activator activity involved in apoptotic process, calcium ion transmembrane transporter activity, calcium-dependent ATPase activity, transmembrane transporter binding.

**Biological process:** intracellular calcium ion homeostasis, intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress, calcium ion transmembrane transport, calcium ion transport from cytosol to endoplasmic reticulum.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-07-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-07-12 |

## Associated conditions {#conditions}

[ATP2A3-related disorder](https://sugi.bio/atlas/disease/atp2a3-related-disorder/).

**Reported phenotype names (ClinVar):** ATP2A3-related disorder, ATP2A3-related condition.

## Similar variants {#similar}

Related ATP2A3 variant pages (same residue, condition, or type): [ATP2A3 c.1095+9C>T](/variant/atp2a3-c-1095-plus-9c-t), [ATP2A3 c.1419+10G>A](/variant/atp2a3-c-1419-plus-10g-a), [ATP2A3 c.1420-4G>A](/variant/atp2a3-c-1420-minus-4g-a), [ATP2A3 c.2863-5G>A](/variant/atp2a3-c-2863-minus-5g-a), [ATP2A3 c.*14A>G](/variant/atp2a3-c-star-14a-g), [ATP2A3 c.*19A>G](/variant/atp2a3-c-star-19a-g), [ATP2A3 p.Ala223=](/variant/atp2a3-p-ala223), [ATP2A3 p.Ala331=](/variant/atp2a3-p-ala331).

### 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 3050071). 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.*