Is ATP7B p.His1069Gln (c.3207C>A) pathogenic?

ATP7B p.His1069Gln (c.3207C>A) is classified Pathogenic in ATP7B (ClinVar, Multiple submitters, 47 submitters; last evaluated 2026-06-01). AlphaMissense: likely pathogenic (0.9933); Rare (popmax 0.106%, nfe); Associated with ATP7B-related disorder.

What condition is associated with ATP7B p.His1069Gln (c.3207C>A)?

ATP7B p.His1069Gln (c.3207C>A) is associated with ATP7B-related disorder, Wilson disease (ClinVar).

How common is ATP7B p.His1069Gln (c.3207C>A) in the general population?

ATP7B p.His1069Gln (c.3207C>A) is rare (popmax 0.106%, nfe) (gnomAD).

What do computational predictors say about ATP7B p.His1069Gln (c.3207C>A)?

AlphaMissense predicts likely pathogenic (score 0.9933) — an in-silico prediction, not a clinical call.

ATP7B p.His1069Gln

c.3207C>A · rs76151636 · VCV3848

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 47 submitters

AlphaMissense

likely pathogenic

0.9933 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.106%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ATP7B-related disorder

Computational evidence

Protein change
AlphaMissense	0.9933	likely pathogenic ✓ concordant with ClinVar · top 3% in ATP7B
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -15.40	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 3.3	GERP -0.95, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.92 · regional, not allelic
Overall
CADD	22.8	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 0.106% European (non-Finnish) · 1,249/1,180,030 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.099%

Overall 0.0944% 1,523/1,614,166 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.527%	190
European (non-Finnish)grpmax	0.106%	945
Remaining individualsnot grpmax-eligible	0.0928%	1,078
Finnishnot grpmax-eligible	0.05%	2,001
Admixed American	0.0417%	2,401
African / African-American	0.004%	25,015

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His1069Gln
Coding: c.3207C>A
MANE Select: NM_000053
dbSNP: rs76151636
Type: single nucleotide variant
Location: chr13:51944145 (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 1069: a UniProt-annotated variant site (in wd; common mutation; decreased copper transport activity; loss of atpase activity; cannot form an acylphosphate intermediate during catalysis; does not alter the folding of the nucleotide-binding domain; decreased stability; does not localize to late endosomes)

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

Disease context

ATP7B-related disorder

Also linked: Wilson disease

Similar variants

ATP7B p.His1069Arg Pathogenic ★★ same residue
ATP7B p.His1069Leu Likely pathogenic ★ same residue
ATP7B p.His1069= Likely benign ★ 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
ATP7B c.1543+1G>C Pathogenic ★★ same condition
ATP7B c.1544-2A>G 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-his1069gln (accessed [today's date]).

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