Is BCHE p.Phe56Ile (c.166T>A) pathogenic?

BCHE p.Phe56Ile (c.166T>A) is classified Conflicting classifications of pathogenicity in BCHE (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-05-12). AlphaMissense: likely pathogenic (0.7366); Ultra-rare (popmax 0.0108%, nfe); Associated with butyrylcholinesterase deficiency.

What condition is associated with BCHE p.Phe56Ile (c.166T>A)?

BCHE p.Phe56Ile (c.166T>A) is associated with butyrylcholinesterase deficiency (ClinVar).

How common is BCHE p.Phe56Ile (c.166T>A) in the general population?

BCHE p.Phe56Ile (c.166T>A) is ultra-rare (popmax 0.0108%, nfe) (gnomAD).

How is Hereditary butyrylcholinesterase deficiency inherited?

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

What do computational predictors say about BCHE p.Phe56Ile (c.166T>A)?

AlphaMissense predicts likely pathogenic (score 0.7366) — an in-silico prediction, not a clinical call.

BCHE p.Phe56Ile

c.166T>A · rs531738678 · VCV631914

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7366 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

butyrylcholinesterase deficiency

Computational evidence

Protein change
AlphaMissense	0.7366	likely pathogenic
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -8.09	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 58 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	27.6	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 0.0108% European (non-Finnish) · 127/1,179,924 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00863%

Overall 0.0083% 134/1,613,868 alleles · ultra-rare exomes 127/1,461,690 · genomes 7/152,178 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0108%	9,291
Remaining individualsnot grpmax-eligible	0.0064%	15,621
African / African-American	0.004%	24,972

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.Phe56Ile
Coding: c.166T>A
MANE Select: NM_000055
dbSNP: rs531738678
Type: single nucleotide variant
Location: chr3:165830868 (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 56: a UniProt-annotated variant site (in bched); a β-strand

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

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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
BCHE p.Tyr528Ter 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-phe56ile (accessed [today's date]).

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