Is ATP7B p.Val374= (c.1122C>G) pathogenic?

ATP7B p.Val374= (c.1122C>G) is classified Conflicting classifications of pathogenicity in ATP7B (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-26). Rare (popmax 0.118%, eas); Associated with Inborn genetic diseases.

What condition is associated with ATP7B p.Val374= (c.1122C>G)?

ATP7B p.Val374= (c.1122C>G) is associated with Inborn genetic diseases, Wilson disease (ClinVar).

How common is ATP7B p.Val374= (c.1122C>G) in the general population?

ATP7B p.Val374= (c.1122C>G) is rare (popmax 0.118%, eas) (gnomAD).

ATP7B p.Val374=

c.1122C>G · rs201254466 · VCV312395

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

rare (popmax 0.118%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -4, phastCons 1
Overall
CADD	5.634	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.118% East Asian · 53/44,862 alleles

Filtering AF 0.0927% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0836%

Overall 0.00651% 105/1,614,008 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.118%	846
South Asian	0.0198%	5,060
Remaining individualsnot grpmax-eligible	0.0176%	5,682
European (non-Finnish)	0.00195%	51,306

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.Val374=
Coding: c.1122C>G
MANE Select: NM_000053
dbSNP: rs201254466
Type: single nucleotide variant
Location: chr13:51974098 (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 374: the hma 4 domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Wilson disease

Similar variants

ATP7B p.Val374Gly Uncertain significance ★ ⚠ 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
ATP7B c.1707+1G>A Pathogenic/Likely pathogenic ★★ same condition
ATP7B c.1707+5G>A 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-val374 (accessed [today's date]).

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