Is BPI p.Ala333Thr (c.997G>A) pathogenic?

BPI p.Ala333Thr (c.997G>A) is classified Likely benign in BPI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-07-17). AlphaMissense: likely benign (0.1081); Rare (popmax 0.48%, mid).

How common is BPI p.Ala333Thr (c.997G>A) in the general population?

BPI p.Ala333Thr (c.997G>A) is rare (popmax 0.48%, mid) (gnomAD).

What do computational predictors say about BPI p.Ala333Thr (c.997G>A)?

AlphaMissense predicts likely benign (score 0.1081) — an in-silico prediction, not a clinical call.

BPI p.Ala333Thr

c.997G>A · rs137967923 · VCV708034

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1081 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.48%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1081	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -9.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.94, phastCons 0.99
Regional constraint	o/e 1.07	unconstrained · MANE · 33 kb · p 0.094 · regional, not allelic
Overall
CADD	14.71	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 A337T vs ClinVar A333T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.48% Middle Eastern · 29/6,046 alleles

Filtering AF 0.369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.365%

Overall 0.319% 5,144/1,611,370 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.48%	208
European (non-Finnish)	0.378%	264
Remaining individualsnot grpmax-eligible	0.277%	361
Admixed American	0.257%	389
South Asian	0.216%	463
Finnishnot grpmax-eligible	0.125%	799
Ashkenazi Jewishnot grpmax-eligible	0.0815%	1,227
African / African-American	0.0401%	2,497

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.Ala333Thr
Coding: c.997G>A
MANE Select: NM_001725
dbSNP: rs137967923
Type: single nucleotide variant
Location: chr20:38326268 (GRCh38)
Gene constraint: LOEUF 1.011 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.70 · 2 PDB
Residue 333: 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.Ala8Thr Benign ★★ same type
BPI p.Ala8Val Benign ★★ same type
BPI p.Arg86Cys Benign ★★ ⚠ same type
BPI p.Glu136Gln Benign ★★ same type
BPI p.Glu212Lys 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-ala333thr (accessed [today's date]).

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