# NM_016529.6(ATP8A2):c.1662G>A (p.Ala554=)

https://sugi.bio/variant/atp8a2-p-ala554

## Summary

**ATP8A2 p.Ala554= (c.1662G>A)** is classified **Uncertain significance** in ATP8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-16). Very rare (popmax 0.00167%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs765757067 · 1 submitter · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the ATP8A2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [ATP8A2](https://sugi.bio/atlas/gene/ATP8A2/) |
| Protein change (HGVS p.) | p.Ala554= |
| Coding change (HGVS c.) | c.1662G>A |
| MANE Select transcript | [NM_016529](https://www.ncbi.nlm.nih.gov/nuccore/NM_016529) |
| dbSNP | [rs765757067](https://www.ncbi.nlm.nih.gov/snp/rs765757067/) |
| Variant type | single nucleotide variant |
| Location | chr13:25571692-25571692 (GRCh38) |
| ClinVar | [VCV1909334](https://www.ncbi.nlm.nih.gov/clinvar/variation/1909334/) |

**All HGVS expressions:** `NC_000013.10:g.26145830G>A`, `NC_000013.11:g.25571692G>A`, `NG_042855.1:g.204682G>A`, `NM_001313741.1:c.1542G>A`, `NM_001411005.1:c.1662G>A`, `NM_001411006.1:c.1662G>A`, `NM_016529.6:c.1662G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -3.882, GERP -3.73 — fast-evolving / accelerated position
- CADD: **PHRED 11.24**. 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 deltas (raw): acceptor loss **0.20**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.48** (loss), gain 0.00 / loss 0.48. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 0.000764% · FAF99 0.000606% · 1/60,002 in the highest group · 18/1,613,310 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 60,002 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,458 |
| African / African-American | 0.00133% | 74,908 |
| European (non-Finnish) | 0.00127% | 78,624 |

*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}

**ATP8A2** population constraint: LOEUF 0.728, pLI 7.9069e-09, missense-Z 1.8645; ClinGen dosage — haploinsufficiency 30, 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):

- **cerebellar ataxia, intellectual disability, and dysequilibrium** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.12, 33% of residues very-high.

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

*Describes the biological roles of ATP8A2 (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.*


### Pathways affected {#pathways}

ATP8A2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Ion transport by P-type ATPases](https://reactome.org/content/detail/R-HSA-936837) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-16 |

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

## Similar variants {#similar}

Related ATP8A2 variant pages (same residue, condition, or type): [ATP8A2 p.Ala554Gly](/variant/atp8a2-p-ala554gly), [ATP8A2 c.1782+2T>C](/variant/atp8a2-c-1782-plus-2t-c), [ATP8A2 c.2212-1G>C](/variant/atp8a2-c-2212-minus-1g-c), [ATP8A2 c.3272+1G>A](/variant/atp8a2-c-3272-plus-1g-a), [ATP8A2 c.77-2A>G](/variant/atp8a2-c-77-minus-2a-g), [ATP8A2 p.Arg586Ter](/variant/atp8a2-p-arg586ter), [ATP8A2 p.Asp765Tyr](/variant/atp8a2-p-asp765tyr), [ATP8A2 p.Ala1091Val](/variant/atp8a2-p-ala1091val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1909334). 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.*