Is BCHE p.Pro309Leu (c.926C>T) pathogenic?

BCHE p.Pro309Leu (c.926C>T) is classified Uncertain significance in BCHE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1007); Very rare (popmax 0.00788%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BCHE p.Pro309Leu (c.926C>T)?

BCHE p.Pro309Leu (c.926C>T) is associated with Inborn genetic diseases (ClinVar).

How common is BCHE p.Pro309Leu (c.926C>T) in the general population?

BCHE p.Pro309Leu (c.926C>T) is very rare (popmax 0.00788%, nfe) (gnomAD).

What do computational predictors say about BCHE p.Pro309Leu (c.926C>T)?

AlphaMissense predicts likely benign (score 0.1007) — an in-silico prediction, not a clinical call.

BCHE p.Pro309Leu

c.926C>T · VCV4828742

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1007 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00788%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1007	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -11.30	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.77, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 58 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	18.77	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 0.00788% European (non-Finnish) · 93/1,179,882 alleles

Filtering AF 0.00656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00608%

Overall 0.00626% 101/1,613,630 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,925
European (non-Finnish)grpmax	0.00788%	12,687
African / African-American	0.00134%	74,858

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro309Leu
Coding: c.926C>T
MANE Select: NM_000055
Type: single nucleotide variant
Location: chr3:165830108 (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 309: a β-strand

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

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BCHE p.Ala444Thr Uncertain significance ★ ⚠ same condition
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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-pro309leu (accessed [today's date]).

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