Is ATP7B p.Ala576Val (c.1727C>T) pathogenic?

ATP7B p.Ala576Val (c.1727C>T) is classified Uncertain significance in ATP7B (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-10). AlphaMissense: ambiguous (0.3658); Very rare (popmax 0.00144%, nfe); Associated with Wilson disease.

What condition is associated with ATP7B p.Ala576Val (c.1727C>T)?

ATP7B p.Ala576Val (c.1727C>T) is associated with Wilson disease (ClinVar).

How common is ATP7B p.Ala576Val (c.1727C>T) in the general population?

ATP7B p.Ala576Val (c.1727C>T) is very rare (popmax 0.00144%, nfe) (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.Ala576Val (c.1727C>T)?

AlphaMissense predicts ambiguous (score 0.3658) — an in-silico prediction, not a clinical call.

ATP7B p.Ala576Val

c.1727C>T · rs778293661 · VCV2141850

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Wilson disease

Computational evidence

Protein change
AlphaMissense	0.3658	ambiguous
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -10.14	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
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	28.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,180,030 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00192% 31/1,614,090 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,691
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	0.00144%	69,414
African / African-American	0.00133%	75,000
South Asian	0.0011%	91,072

Ashkenazi Jewish 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.Ala576Val
Coding: c.1727C>T
MANE Select: NM_000053
dbSNP: rs778293661
Type: single nucleotide variant
Location: chr13:51965014 (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 576: the hma 6 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.Ala576Thr Uncertain significance ★ ⚠ same residue
ATP7B p.Ala576= Likely benign ★ same residue
ATP7B p.Ala576fs 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-ala576val (accessed [today's date]).

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