Is BCHE p.Phe365Leu (c.1095C>G) pathogenic?

BCHE p.Phe365Leu (c.1095C>G) is classified Uncertain significance in BCHE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely pathogenic (0.9247); Ultra-rare (popmax 0.012%, afr); Associated with Inborn genetic diseases.

What condition is associated with BCHE p.Phe365Leu (c.1095C>G)?

BCHE p.Phe365Leu (c.1095C>G) is associated with Inborn genetic diseases (ClinVar).

How common is BCHE p.Phe365Leu (c.1095C>G) in the general population?

BCHE p.Phe365Leu (c.1095C>G) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about BCHE p.Phe365Leu (c.1095C>G)?

AlphaMissense predicts likely pathogenic (score 0.9247) — an in-silico prediction, not a clinical call.

BCHE p.Phe365Leu

c.1095C>G · rs139312740 · VCV2620630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9247 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9247	likely pathogenic · top 3% in BCHE
REVEL	0.171	moderately benign-leaning
SaProt	LLR -10.13	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.24, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 58 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	21.1	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 0.012% African / African-American · 9/74,834 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.000558% 9/1,613,308 alleles · ultra-rare

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.Phe365Leu
Coding: c.1095C>G
MANE Select: NM_000055
dbSNP: rs139312740
Type: single nucleotide variant
Location: chr3:165829939 (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

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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-phe365leu (accessed [today's date]).

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