Is ATP7B p.Pro992= (c.2976C>A) pathogenic?

ATP7B p.Pro992= (c.2976C>A) is classified Conflicting classifications of pathogenicity in ATP7B (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-09-29). Ultra-rare (popmax 0.0341%, sas); Associated with Wilson disease.

What condition is associated with ATP7B p.Pro992= (c.2976C>A)?

ATP7B p.Pro992= (c.2976C>A) is associated with Wilson disease (ClinVar).

How common is ATP7B p.Pro992= (c.2976C>A) in the general population?

ATP7B p.Pro992= (c.2976C>A) is ultra-rare (popmax 0.0341%, sas) (gnomAD).

How is Wilson disease inherited?

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

ATP7B p.Pro992=

c.2976C>A · rs746358240 · VCV254766

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0341%, sas)

Conditions

Wilson disease

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 1.4	GERP -3.2, phastCons 1
Overall
CADD	7.972	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0341% South Asian · 31/90,974 alleles

Filtering AF 0.0247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00205% 33/1,613,344 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0341%	2,935
Remaining individualsnot grpmax-eligible	0.0032%	31,217

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.Pro992=
Coding: c.2976C>A
MANE Select: NM_000053
dbSNP: rs746358240
Type: single nucleotide variant
Location: chr13:51946368 (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 992: a UniProt-annotated variant site (in wd); a UniProt-annotated variant site (in wd; common mutation; decreased copper transport activity; no effect on atpase activity); 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.Pro992His Uncertain significance ★ ⚠ same residue
ATP7B p.Pro992Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ATP7B p.Pro992fs 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
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-pro992 (accessed [today's date]).

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