Is BCHE p.Leu358Ile (c.1072T>A) pathogenic?

BCHE p.Leu358Ile (c.1072T>A) is classified Pathogenic/Likely pathogenic in BCHE (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-01-13). AlphaMissense: likely benign (0.1335); Rare (popmax 0.27%, eas); Associated with butyrylcholinesterase deficiency.

What condition is associated with BCHE p.Leu358Ile (c.1072T>A)?

BCHE p.Leu358Ile (c.1072T>A) is associated with butyrylcholinesterase deficiency (ClinVar).

How common is BCHE p.Leu358Ile (c.1072T>A) in the general population?

BCHE p.Leu358Ile (c.1072T>A) is rare (popmax 0.27%, eas) (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.Leu358Ile (c.1072T>A)?

AlphaMissense predicts likely benign (score 0.1335) — an in-silico prediction, not a clinical call.

BCHE p.Leu358Ile

c.1072T>A · rs121918557 · VCV13226

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1335 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.27%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

butyrylcholinesterase deficiency

Computational evidence

Protein change
AlphaMissense	0.1335	likely benign ⚠ discordant with ClinVar
REVEL	0.365	indeterminate
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -2.2, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 58 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	19.48	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 0.27% East Asian · 121/44,860 alleles

Filtering AF 0.231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.216%

Overall 0.00812% 131/1,613,798 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.27%	371
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0064%	15,622
South Asian	0.0011%	91,074
European (non-Finnish)	0.000339%	294,973

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.Leu358Ile
Coding: c.1072T>A
MANE Select: NM_000055
dbSNP: rs121918557
Type: single nucleotide variant
Location: chr3:165829962 (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 358: an α-helix; a UniProt-annotated variant site (in bched; bche variant form; fluoride-resistant)

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.Leu358fs Likely pathogenic 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.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-leu358ile (accessed [today's date]).

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