Is ATP7B p.Leu732Phe (c.2194C>T) pathogenic?

ATP7B p.Leu732Phe (c.2194C>T) is classified Uncertain significance in ATP7B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.9889); Very rare (popmax 0.0022%, sas); Associated with Wilson disease.

What condition is associated with ATP7B p.Leu732Phe (c.2194C>T)?

ATP7B p.Leu732Phe (c.2194C>T) is associated with Wilson disease (ClinVar).

How common is ATP7B p.Leu732Phe (c.2194C>T) in the general population?

ATP7B p.Leu732Phe (c.2194C>T) is very rare (popmax 0.0022%, sas) (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.Leu732Phe (c.2194C>T)?

AlphaMissense predicts likely pathogenic (score 0.9889) — an in-silico prediction, not a clinical call.

ATP7B p.Leu732Phe

c.2194C>T · rs1958502647 · VCV1021167

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Wilson disease

Computational evidence

Protein change
AlphaMissense	0.9889	likely pathogenic · top 5% in ATP7B
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -12.85	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 12	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.92 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0022% South Asian · 2/91,080 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000205% 3/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,540
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Leu732Phe
Coding: c.2194C>T
MANE Select: NM_000053
dbSNP: rs1958502647
Type: single nucleotide variant
Location: chr13:51958472 (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 732: a UniProt-annotated variant site (in wd; uncertain significance); 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.Leu732= 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
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-leu732phe (accessed [today's date]).

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