Is BCHE p.Tyr528Ter (c.1584T>A) pathogenic?

BCHE p.Tyr528Ter (c.1584T>A) is classified Pathogenic/Likely pathogenic in BCHE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-28). Ultra-rare (popmax 0.0351%, amr); Associated with butyrylcholinesterase deficiency.

What condition is associated with BCHE p.Tyr528Ter (c.1584T>A)?

BCHE p.Tyr528Ter (c.1584T>A) is associated with butyrylcholinesterase deficiency (ClinVar).

How common is BCHE p.Tyr528Ter (c.1584T>A) in the general population?

BCHE p.Tyr528Ter (c.1584T>A) is ultra-rare (popmax 0.0351%, amr) (gnomAD).

How is Hereditary butyrylcholinesterase deficiency inherited?

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

BCHE p.Tyr528Ter

c.1584T>A · rs760485585 · VCV555346

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, amr)

Conditions

butyrylcholinesterase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 4
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.9, phastCons 0.99
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0351% Admixed American · 21/59,864 alleles

Filtering AF 0.0235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0013% 21/1,612,144 alleles · ultra-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: BCHE
Protein: p.Tyr528Ter
Coding: c.1584T>A
MANE Select: NM_000055
dbSNP: rs760485585
Type: single nucleotide variant
Location: chr3:165786245 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.30 · 111 PDB
Residue 528: a β-strand; a disulfide bond

Full BCHE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

butyrylcholinesterase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary butyrylcholinesterase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

BCHE p.Tyr528Phe Uncertain significance ★ ⚠ same residue
BCHE p.Arg414Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
BCHE p.Arg452Ter Pathogenic/Likely pathogenic ★★ same condition
BCHE p.Asp98Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
BCHE p.Glu377Ter Pathogenic/Likely pathogenic ★★ same condition
BCHE p.Gly143Asp Pathogenic ★★ same condition
BCHE p.Gly393Arg Pathogenic ★★ same condition
BCHE p.Leu358Ile 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/bche-p-tyr528ter (accessed [today's date]).

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