Is ATP7B p.Ser391fs (c.1172del) pathogenic?

ATP7B p.Ser391fs (c.1172del) is classified Pathogenic/Likely pathogenic in ATP7B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-16). Very rare (popmax 0.00133%, afr); Associated with Wilson disease.

What condition is associated with ATP7B p.Ser391fs (c.1172del)?

ATP7B p.Ser391fs (c.1172del) is associated with Wilson disease (ClinVar).

How common is ATP7B p.Ser391fs (c.1172del) in the general population?

ATP7B p.Ser391fs (c.1172del) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Wilson disease inherited?

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

ATP7B p.Ser391fs

c.1172del · rs1951978776 · VCV2163518

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Wilson disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -6	GERP -4

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,048 alleles

Overall 6.84e-05% 1/1,461,892 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.Ser391fs
Coding: c.1172del
MANE Select: NM_000053
dbSNP: rs1951978776
Type: Deletion
Location: chr13:51974048 (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 391: the hma 4 domain; a β-strand

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.Ser391Pro Uncertain significance ★★ ⚠ same residue
ATP7B p.Ser391Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ATP7B p.Ser391= Likely benign ★ same residue
ATP7B c.1700_1707+16del Likely pathogenic ★★ same condition
ATP7B c.1705_1707+10del Pathogenic ★★ same condition
ATP7B c.2866-2del Pathogenic/Likely pathogenic ★★ same condition
ATP7B c.3700del Pathogenic ★★ same condition
ATP7B c.3904-2del 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-ser391fs (accessed [today's date]).

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