Is ATP7B p.Asp765His (c.2293G>C) pathogenic?

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.

What condition is associated with ATP7B p.Asp765His (c.2293G>C)?

ATP7B p.Asp765His (c.2293G>C) is associated with Wilson disease (ClinVar).

How common is ATP7B p.Asp765His (c.2293G>C) in the general population?

ATP7B p.Asp765His (c.2293G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Wilson disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ATP7B p.Asp765His (c.2293G>C)?

AlphaMissense predicts likely pathogenic (score 0.9722) — an in-silico prediction, not a clinical call.

ATP7B p.Asp765His

c.2293G>C · VCV3387730

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Wilson disease

Computational evidence

Protein change
AlphaMissense	0.9722	likely pathogenic ✓ concordant with ClinVar · top 8% in ATP7B
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -13.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.92 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,014 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,878 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ATP7B
Protein: p.Asp765His
Coding: c.2293G>C
MANE Select: NM_000053
Type: single nucleotide variant
Location: chr13:51958373 (GRCh38)
Gene constraint: LOEUF 1.063 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.83 · 13 PDB
Residue 765: 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)

Full ATP7B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Wilson disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Wilson disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

ATP7B p.Asp765Asn Pathogenic/Likely pathogenic ★★ same residue
ATP7B p.Asp765Gly Pathogenic/Likely pathogenic ★★ same residue
ATP7B p.Asp765= Likely benign ★★ same residue
ATP7B p.Asp765Glu Likely pathogenic ★ ⚠ same residue
ATP7B p.Asp765_Phe771del Pathogenic/Likely pathogenic ★★ same residue
ATP7B c.1285+2T>A Pathogenic/Likely pathogenic ★★ same condition
ATP7B c.1286-2A>G Pathogenic ★★ same condition
ATP7B c.1543+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/atp7b-p-asp765his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown