# NM_000053.4(ATP7B):c.2730G>A (p.Lys910=)

https://sugi.bio/variant/atp7b-p-lys910

## Summary

**ATP7B p.Lys910= (c.2730G>A)** is classified **Conflicting classifications of pathogenicity** in ATP7B (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-15). Rare (popmax 0.115%, afr); Associated with Wilson disease.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs80145681 · 7 submitters · 1 linked condition · rare (popmax 0.115%, afr)

## For patients & families {#patients}

This is a change in the ATP7B gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to Wilson disease.

*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 recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Elderly |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 70 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ATP7B is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of Wilson disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Gait disturbance — Very frequent (99-80%)
- Amplification of sexual behavior — Very frequent (99-80%)
- Abnormality of the menstrual cycle — Very frequent (99-80%)
- Depression — Very frequent (99-80%)
- Aggressive behavior — Very frequent (99-80%)
- Jaundice — Very frequent (99-80%)
- Bruising susceptibility — Very frequent (99-80%)
- Pruritus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007893/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ATP7B](https://sugi.bio/atlas/gene/ATP7B/) |
| Protein change (HGVS p.) | p.Lys910= |
| Coding change (HGVS c.) | c.2730G>A |
| MANE Select transcript | [NM_000053](https://www.ncbi.nlm.nih.gov/nuccore/NM_000053) |
| dbSNP | [rs80145681](https://www.ncbi.nlm.nih.gov/snp/rs80145681/) |
| Variant type | single nucleotide variant |
| Location | chr13:51950007-51950007 (GRCh38) |
| ClinVar | [VCV991418](https://www.ncbi.nlm.nih.gov/clinvar/variation/991418/) |

**All HGVS expressions:** `NC_000013.10:g.52524143C>T`, `NC_000013.11:g.51950007C>T`, `NG_008806.1:g.66488G>A`, `NM_000053.3:c.2730G>A`, `NM_000053.4:c.2730G>A`, `NM_001005918.3:c.2244G>A`, `NM_001243182.2:c.2397G>A`, `NM_001330578.2:c.2496G>A`, `NM_001330579.2:c.2478G>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 0.31) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 7.591, GERP 2.02, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.0**. 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 **0.00**, donor loss **0.31**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.29** (loss), gain 0.03 / loss 0.29. 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 **0.115%** (afr) · FAF95 0.095% · FAF99 0.0878% · 86/75,028 in the highest group · 104/1,614,154 alleles overall — rare (popmax 0.115%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.115% | 872 |
| Remaining individuals (not grpmax-eligible) | 0.0144% | 6,946 |
| Admixed American | 0.00833% | 12,005 |
| European (non-Finnish) | 0.000339% | 295,007 |

*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}

**ATP7B** population constraint: LOEUF 1.063, pLI 1.0828e-35, missense-Z 0.83587; 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):

- **Wilson disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 71.83, 11% of residues very-high.

**13 experimental structure(s)** (PDB): [2ARF](https://www.rcsb.org/structure/2ARF), [2EW9](https://www.rcsb.org/structure/2EW9), [2KOY](https://www.rcsb.org/structure/2KOY), [2LQB](https://www.rcsb.org/structure/2LQB), [2N7Y](https://www.rcsb.org/structure/2N7Y), [2ROP](https://www.rcsb.org/structure/2ROP) — incl. mutant structure 2KOY.

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

*Describes the biological roles of ATP7B (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:** ATP7B's established molecular role includes copper ion transmembrane transporter activity.


### Pathways affected {#pathways}

ATP7B 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 |

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

**Molecular function:** copper ion transmembrane transporter activity, copper ion binding, ATP binding, P-type monovalent copper transporter activity.

**Biological process:** copper ion transport, copper ion import, response to copper ion, obsolete sequestering of calcium ion.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-15.

**Submitter consensus:** conflicting (5 Uncertain significance, 1 Uncertain Significance, 1 Likely benign).

**Submission history:** 7 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-04-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-22 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-21 |
| All of Us Research Program, National Institutes of Health | Uncertain Significance | criteria provided, single submitter | clinical testing | 2024-01-11 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-29 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-15 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-06 |

## Associated conditions {#conditions}

[Wilson disease](https://sugi.bio/atlas/disease/wilson-disease/).

**Reported phenotype names (ClinVar):** Wilson disease, not provided, Wilson's disease, none provided.

## Similar variants {#similar}

Related ATP7B variant pages (same residue, condition, or type): [ATP7B c.1285+2T>A](/variant/atp7b-c-1285-plus-2t-a), [ATP7B c.1286-2A>G](/variant/atp7b-c-1286-minus-2a-g), [ATP7B c.1543+1G>A](/variant/atp7b-c-1543-plus-1g-a), [ATP7B c.1543+1G>C](/variant/atp7b-c-1543-plus-1g-c), [ATP7B c.1544-2A>G](/variant/atp7b-c-1544-minus-2a-g), [ATP7B c.1707+1G>A](/variant/atp7b-c-1707-plus-1g-a), [ATP7B c.1707+5G>A](/variant/atp7b-c-1707-plus-5g-a), [ATP7B c.1708-1G>A](/variant/atp7b-c-1708-minus-1g-a).

### 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 991418). 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.*