# NM_000053.4(ATP7B):c.2293G>C (p.Asp765His)

https://sugi.bio/variant/atp7b-p-asp765his

## Summary

**ATP7B p.Asp765His (c.2293G>C)** is classified **Pathogenic/Likely pathogenic** in ATP7B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.9722); Very rare (popmax 0.000254%, nfe); Associated with Wilson disease.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the ATP7B gene that is considered likely disease-causing, submitted by 3 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.Asp765His |
| Coding change (HGVS c.) | c.2293G>C |
| MANE Select transcript | [NM_000053](https://www.ncbi.nlm.nih.gov/nuccore/NM_000053) |
| Variant type | single nucleotide variant |
| Location | chr13:51958373-51958373 (GRCh38) |
| ClinVar | [VCV3387730](https://www.ncbi.nlm.nih.gov/clinvar/variation/3387730/) |

**All HGVS expressions:** `NC_000013.10:g.52532509C>G`, `NC_000013.11:g.51958373C>G`, `NG_008806.1:g.58122G>C`, `NM_000053.4:c.2293G>C`, `NM_001005918.3:c.1870-766G>C`, `NM_001243182.2:c.1960G>C`, `NM_001330578.2:c.2122-766G>C`, `NM_001330579.2:c.2041G>C`, `NM_001406511.1:c.2293G>C`, `NM_001406512.1:c.2293G>C`, `NM_001406513.1:c.2293G>C`, `NM_001406514.1:c.2260G>C`, `NM_001406515.1:c.2293G>C`, `NM_001406516.1:c.2293G>C`, `NM_001406517.1:c.2197G>C`, `NM_001406518.1:c.2197G>C`, `NM_001406519.1:c.2293G>C`, `NM_001406520.1:c.2149G>C`, `NM_001406521.1:c.2149G>C`, `NM_001406522.1:c.2149G>C`, `NM_001406523.1:c.2293G>C`, `NM_001406524.1:c.2116G>C`, `NM_001406525.1:c.2293G>C`, `NM_001406526.1:c.2293G>C`, `NM_001406527.1:c.2122-766G>C`, `NM_001406528.1:c.2122-766G>C`, `NM_001406530.1:c.2053G>C`, `NM_001406531.1:c.2041G>C`, `NM_001406532.1:c.2041G>C`, `NM_001406534.1:c.2122-766G>C`, `NM_001406535.1:c.2293G>C`, `NM_001406536.1:c.2026-766G>C`, `NM_001406537.1:c.2149G>C`, `NM_001406538.1:c.2122-766G>C`, `NM_001406539.1:c.1864G>C`, `NM_001406540.1:c.2041G>C`, `NM_001406541.1:c.1870-766G>C`, `NM_001406542.1:c.1870-766G>C`, `NM_001406543.1:c.1945G>C`, `NM_001406544.1:c.1774-766G>C`, `NM_001406545.1:c.1708-766G>C`, `NM_001406546.1:c.1870-766G>C`, `NM_001406547.1:c.1708-766G>C`, `NM_001406548.1:c.1286-8212G>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9722) — concordant with the pathogenic call
- REVEL 0.954 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.797 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.566, GERP 2.02, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in ATP7B (of 8,668 modeled).
- CADD: **PHRED 27.2**. 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 1.00** across the covering region of the MANE Select transcript (51,934,759–52,011,337), spanning 76,578 bp. Chi-square p 0.92. 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 (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,180,014 in the highest group · 3/1,461,878 alleles overall — very rare (popmax 0.000254%, 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}

**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}

Residue **765** lies in a UniProt-annotated variant site (in wd); a UniProt-annotated variant site (in wd; uncertain significance); a UniProt-annotated variant site (in wd; decreased copper transport activity; increased atpase activity; decreased localization to tgn and reduced capacity to redistribute to cytoplasmic vesicles under high-copper levels).

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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-01.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely Pathogenic).

**Submission history:** 3 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| All of Us Research Program, National Institutes of Health | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-11 |
| Lildballe Lab, Aarhus University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-29 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-01 |

## 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.

## Same-residue context {#hotspot}

Residue **765** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [ATP7B p.Asp765Glu](/variant/atp7b-p-asp765glu), [ATP7B p.Asp765_Phe771del](/variant/atp7b-p-asp765-phe771del), [ATP7B p.Asp765Asn](/variant/atp7b-p-asp765asn), [ATP7B p.Asp765Gly](/variant/atp7b-p-asp765gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ATP7B variant pages (same residue, condition, or type): [ATP7B p.Asp765Asn](/variant/atp7b-p-asp765asn), [ATP7B p.Asp765Gly](/variant/atp7b-p-asp765gly), [ATP7B p.Asp765=](/variant/atp7b-p-asp765), [ATP7B p.Asp765Glu](/variant/atp7b-p-asp765glu), [ATP7B p.Asp765_Phe771del](/variant/atp7b-p-asp765-phe771del), [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).

### 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 3387730). 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.*