Is ATP7B p.Phe206Leu (c.618T>A) pathogenic?

ATP7B p.Phe206Leu (c.618T>A) is classified Uncertain significance in ATP7B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-24). AlphaMissense: likely pathogenic (0.9885); Very rare (popmax 8.48e-05%, nfe); Associated with Wilson disease.

What condition is associated with ATP7B p.Phe206Leu (c.618T>A)?

ATP7B p.Phe206Leu (c.618T>A) is associated with Wilson disease (ClinVar).

How common is ATP7B p.Phe206Leu (c.618T>A) in the general population?

ATP7B p.Phe206Leu (c.618T>A) is very rare (popmax 8.48e-05%, 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.Phe206Leu (c.618T>A)?

AlphaMissense predicts likely pathogenic (score 0.9885) — an in-silico prediction, not a clinical call.

ATP7B p.Phe206Leu

c.618T>A · rs764353593 · VCV312399

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9885 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Wilson disease

Computational evidence

Protein change
AlphaMissense	0.9885	likely pathogenic · top 5% in ATP7B
REVEL	0.738	pathogenic-leaning
SaProt	LLR -13.28	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 0.22	GERP -1.6, phastCons 0.2
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.92 · regional, not allelic
Overall
CADD	20.5	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 8.48e-05% European (non-Finnish) · 1/1,179,840 alleles

Overall 6.84e-05% 1/1,461,490 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.Phe206Leu
Coding: c.618T>A
MANE Select: NM_000053
dbSNP: rs764353593
Type: single nucleotide variant
Location: chr13:51974602 (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 206: the hma 2 domain

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.Phe206= 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-phe206leu (accessed [today's date]).

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