Is BCHE p.Leu335Pro (c.1004T>C) pathogenic?

BCHE p.Leu335Pro (c.1004T>C) is classified Conflicting classifications of pathogenicity in BCHE (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.4533); Rare (popmax 0.2%, sas); Associated with butyrylcholinesterase deficiency.

What condition is associated with BCHE p.Leu335Pro (c.1004T>C)?

BCHE p.Leu335Pro (c.1004T>C) is associated with butyrylcholinesterase deficiency (ClinVar).

How common is BCHE p.Leu335Pro (c.1004T>C) in the general population?

BCHE p.Leu335Pro (c.1004T>C) is rare (popmax 0.2%, sas) (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.Leu335Pro (c.1004T>C)?

AlphaMissense predicts ambiguous (score 0.4533) — an in-silico prediction, not a clinical call.

BCHE p.Leu335Pro

c.1004T>C · rs104893684 · VCV13228

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.4533 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.2%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

butyrylcholinesterase deficiency

Computational evidence

Protein change
AlphaMissense	0.4533	ambiguous
REVEL	0.735	pathogenic-leaning
SaProt	LLR -14.63	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 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 58 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	24.5	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 0.2% South Asian · 182/91,062 alleles

Filtering AF 0.176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.167%

Overall 0.0121% 195/1,613,792 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.2%	500
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Middle Eastern	0.0165%	6,060
European (non-Finnish)	8.48e-05%	1,179,892

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.Leu335Pro
Coding: c.1004T>C
MANE Select: NM_000055
dbSNP: rs104893684
Type: single nucleotide variant
Location: chr3:165830030 (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 335: an α-helix; a UniProt-annotated variant site (in bched; expressed at very low level)

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.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
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-leu335pro (accessed [today's date]).

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