Is BCHE p.Ser594Ile (c.1781G>T) pathogenic?

BCHE p.Ser594Ile (c.1781G>T) is classified Uncertain significance in BCHE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-21). AlphaMissense: likely benign (0.1429); Ultra-rare (popmax 0.0829%, afr); Associated with Inborn genetic diseases.

What condition is associated with BCHE p.Ser594Ile (c.1781G>T)?

BCHE p.Ser594Ile (c.1781G>T) is associated with Inborn genetic diseases (ClinVar).

How common is BCHE p.Ser594Ile (c.1781G>T) in the general population?

BCHE p.Ser594Ile (c.1781G>T) is ultra-rare (popmax 0.0829%, afr) (gnomAD).

What do computational predictors say about BCHE p.Ser594Ile (c.1781G>T)?

AlphaMissense predicts likely benign (score 0.1429) — an in-silico prediction, not a clinical call.

BCHE p.Ser594Ile

c.1781G>T · rs142859898 · VCV2273945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1429 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0829%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1429	likely benign
REVEL	0.564	indeterminate
SaProt	LLR -7.20	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 2.2	GERP 0.32, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 58 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0829% African / African-American · 62/74,830 alleles

Filtering AF 0.0662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0603%

Overall 0.00435% 70/1,610,656 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0829%	1,207
Admixed American	0.00668%	14,969
Remaining individualsnot grpmax-eligible	0.00481%	20,774
European (non-Finnish)	8.49e-05%	1,177,627

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.Ser594Ile
Coding: c.1781G>T
MANE Select: NM_000055
dbSNP: rs142859898
Type: single nucleotide variant
Location: chr3:165773410 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.30 · 111 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BCHE p.Ile538Thr Uncertain significance ★★ ⚠ same condition
BCHE p.Met109Ile Uncertain significance ★★ ⚠ same condition
BCHE p.Ser515Thr Uncertain significance ★★ ⚠ same condition
BCHE p.Ala430Asp Uncertain significance ★ ⚠ same condition
BCHE p.Ala444Thr Uncertain significance ★ ⚠ same condition
BCHE p.Ala544Pro Uncertain significance ★ ⚠ same condition
BCHE p.Ala544Val Uncertain significance ★ ⚠ same condition
BCHE p.Ala567Val Uncertain significance ★ ⚠ 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-ser594ile (accessed [today's date]).

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