Is BPI p.Asp309Glu (c.927T>A) pathogenic?

BPI p.Asp309Glu (c.927T>A) is classified Uncertain significance in BPI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: ambiguous (0.5365); Ultra-rare (popmax 0.0171%, mid).

How common is BPI p.Asp309Glu (c.927T>A) in the general population?

BPI p.Asp309Glu (c.927T>A) is ultra-rare (popmax 0.0171%, mid) (gnomAD).

What do computational predictors say about BPI p.Asp309Glu (c.927T>A)?

AlphaMissense predicts ambiguous (score 0.5365) — an in-silico prediction, not a clinical call.

BPI p.Asp309Glu

c.927T>A · VCV3825130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5365 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5365	ambiguous
REVEL	0.121	moderately benign-leaning
SaProt	LLR -8.05	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -4.7
Regional constraint	o/e 1.07	unconstrained · MANE · 33 kb · p 0.094 · regional, not allelic
Overall
CADD	0.121	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM D313E vs ClinVar D309E) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0171% Middle Eastern · 1/5,834 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00347% 56/1,613,594 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0171%	5,834
Remaining individualsnot grpmax-eligible	0.00481%	20,809
European (non-Finnish)	0.00415%	24,081
South Asian	0.0033%	30,347

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: BPI
Protein: p.Asp309Glu
Coding: c.927T>A
MANE Select: NM_001725
Type: single nucleotide variant
Location: chr20:38324040 (GRCh38)
Gene constraint: LOEUF 1.011 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.70 · 2 PDB
Residue 309: the 'c-terminal barrel' region; a β-strand

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

Similar variants

BPI c.664+7G>T Benign ★★ same type
BPI p.Ala12Val Benign ★★ same type
BPI p.Ala192Val Benign ★★ same type
BPI p.Ala333Thr Likely benign ★★ ⚠ same type
BPI p.Ala8Thr Benign ★★ same type
BPI p.Ala8Val Benign ★★ same type
BPI p.Arg86Cys Benign ★★ ⚠ same type
BPI p.Glu136Gln Benign ★★ same type

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/bpi-p-asp309glu (accessed [today's date]).

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