# NM_000055.4(BCHE):c.594T>G (p.Asp198Glu)

https://sugi.bio/variant/bche-p-asp198glu

## Summary

**BCHE p.Asp198Glu (c.594T>G)** is classified **Likely pathogenic** in BCHE (ClinVar, Single submitter, 2 submitters; last evaluated 2022-03-28). AlphaMissense: likely pathogenic (0.9311); Very rare (popmax 0.00703%, nfe); Associated with butyrylcholinesterase deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs781368801 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00703%, nfe)

## For patients & families {#patients}

This is a change in the BCHE gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to butyrylcholinesterase deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of Hereditary butyrylcholinesterase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Respiratory failure — Frequent (79-30%)
- Abnormality of the liver — Very rare (<4-1%)
- Congestive heart failure — Very rare (<4-1%)
- Myocardial infarction — Very rare (<4-1%)
- Neoplasm — Very rare (<4-1%)
- Paralysis — Very rare (<4-1%)
- Respiratory failure requiring assisted ventilation — Very rare (<4-1%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007482/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BCHE](https://sugi.bio/atlas/gene/BCHE/) |
| Protein change (HGVS p.) | p.Asp198Glu |
| Coding change (HGVS c.) | c.594T>G |
| MANE Select transcript | [NM_000055](https://www.ncbi.nlm.nih.gov/nuccore/NM_000055) |
| dbSNP | [rs781368801](https://www.ncbi.nlm.nih.gov/snp/rs781368801/) |
| Variant type | single nucleotide variant |
| Location | chr3:165830440-165830440 (GRCh38) |
| ClinVar | [VCV1677196](https://www.ncbi.nlm.nih.gov/clinvar/variation/1677196/) |

**All HGVS expressions:** `NC_000003.11:g.165548228A>C`, `NC_000003.12:g.165830440A>C`, `NG_009031.1:g.12026T>G`, `NM_000055.4:c.594T>G`, `NR_137636.2:n.712T>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9311) — concordant with the pathogenic call
- REVEL 0.922 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.214 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 1.138, GERP -5.01, phastCons 0.997 — weakly conserved position
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in BCHE (of 3,516 modeled).
- CADD: **PHRED 20.7**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.20** across the covering region of the MANE Select transcript (165,773,385–165,831,033), spanning 57,648 bp. Chi-square p 1.8e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00703%** (nfe) · FAF95 0.00579% · FAF99 0.00533% · 83/1,179,886 in the highest group · 89/1,613,642 alleles overall — very rare (popmax 0.00703%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00703% | 14,215 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,616 |
| Admixed American | 0.00167% | 59,906 |
| African / African-American | 0.00134% | 74,874 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BCHE** population constraint: LOEUF 1.195, pLI 6.4275e-16, missense-Z -1.274; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **198** lies in a UniProt-annotated variant site (in bched; seems to cause reduced expression of the protein); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.30, 83% of residues very-high.

**111 experimental structure(s)** (PDB): [1P0I](https://www.rcsb.org/structure/1P0I), [1P0M](https://www.rcsb.org/structure/1P0M), [1P0P](https://www.rcsb.org/structure/1P0P), [1P0Q](https://www.rcsb.org/structure/1P0Q), [1XLU](https://www.rcsb.org/structure/1XLU), [1XLV](https://www.rcsb.org/structure/1XLV) — incl. mutant structure 2XMB.

## What this gene does {#gene-function}

*Describes the biological roles of BCHE (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BCHE's established molecular role includes cholinesterase activity.


### Pathways affected {#pathways}

BCHE participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Aspirin ADME](https://reactome.org/content/detail/R-HSA-9749641) | curated |
| [Neurotransmitter clearance](https://reactome.org/content/detail/R-HSA-112311) | curated |
| [Synthesis of PC](https://reactome.org/content/detail/R-HSA-1483191) | curated |
| [Synthesis, secretion, and deacylation of Ghrelin](https://reactome.org/content/detail/R-HSA-422085) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** cholinesterase activity, identical protein binding.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-28.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-28 |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-09-19 |

## Associated conditions {#conditions}

[butyrylcholinesterase deficiency](https://sugi.bio/atlas/disease/butyrylcholinesterase-deficiency/).

**Reported phenotype names (ClinVar):** Deficiency of butyrylcholinesterase, BCHE-related disorder, BCHE-related condition, BCHE, silent 1, Acholinesterasemia, Butyrylcholinesterase deficiency, Deficiency of butyrylcholine esterase.

## Similar variants {#similar}

Related BCHE variant pages (same residue, condition, or type): [BCHE p.Arg414Cys](/variant/bche-p-arg414cys), [BCHE p.Arg452Ter](/variant/bche-p-arg452ter), [BCHE p.Asp98Gly](/variant/bche-p-asp98gly), [BCHE p.Glu377Ter](/variant/bche-p-glu377ter), [BCHE p.Gly143Asp](/variant/bche-p-gly143asp), [BCHE p.Gly393Arg](/variant/bche-p-gly393arg), [BCHE p.Leu358Ile](/variant/bche-p-leu358ile), [BCHE p.Tyr528Ter](/variant/bche-p-tyr528ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1677196). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*