Is ATP7B p.Arg919Gln (c.2756G>A) pathogenic?

ATP7B p.Arg919Gln (c.2756G>A) is classified Uncertain significance in ATP7B (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1129); Very rare (popmax 0.00333%, amr); Associated with Wilson disease.

What condition is associated with ATP7B p.Arg919Gln (c.2756G>A)?

ATP7B p.Arg919Gln (c.2756G>A) is associated with Wilson disease (ClinVar).

How common is ATP7B p.Arg919Gln (c.2756G>A) in the general population?

ATP7B p.Arg919Gln (c.2756G>A) is very rare (popmax 0.00333%, amr) (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.Arg919Gln (c.2756G>A)?

AlphaMissense predicts likely benign (score 0.1129) — an in-silico prediction, not a clinical call.

ATP7B p.Arg919Gln

c.2756G>A · rs574579593 · VCV971794

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1129 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Wilson disease

Computational evidence

Protein change
AlphaMissense	0.1129	likely benign
REVEL	0.372	indeterminate
SaProt	LLR -8.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 0.88, phastCons 0.89
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.92 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,020 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00242% 39/1,614,000 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00939%	10,652
Admixed Americangrpmax	0.00333%	30,010
South Asian	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0032%	31,252
European (non-Finnish)	0.0022%	45,385

Finnish 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.Arg919Gln
Coding: c.2756G>A
MANE Select: NM_000053
dbSNP: rs574579593
Type: single nucleotide variant
Location: chr13:51949771 (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 919: a UniProt-annotated variant site (in wd); an α-helix

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.Arg919Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
ATP7B p.Arg919Leu Likely pathogenic ★ ⚠ same residue
ATP7B p.Arg919Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
ATP7B p.Arg919= Likely benign ★ same residue
ATP7B p.Arg919fs 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-arg919gln (accessed [today's date]).

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