Is BPI p.Lys334Arg (c.1001A>G) pathogenic?

BPI p.Lys334Arg (c.1001A>G) is classified Uncertain significance in BPI (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: likely benign (0.0747); Very rare (popmax 0.00263%, nfe).

How common is BPI p.Lys334Arg (c.1001A>G) in the general population?

BPI p.Lys334Arg (c.1001A>G) is very rare (popmax 0.00263%, nfe) (gnomAD).

What do computational predictors say about BPI p.Lys334Arg (c.1001A>G)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

BPI p.Lys334Arg

c.1001A>G · rs775959420 · VCV2588618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -5.99	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 -2	GERP -4
Regional constraint	o/e 1.07	unconstrained · MANE · 33 kb · p 0.094 · regional, not allelic
Overall
CADD	5.505	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K338R vs ClinVar K334R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00263% European (non-Finnish) · 31/1,178,964 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00217% 35/1,612,016 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00679%	14,735
Remaining individualsnot grpmax-eligible	0.0032%	31,207
European (non-Finnish)grpmax	0.00263%	38,031

Ashkenazi Jewish 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: BPI
Protein: p.Lys334Arg
Coding: c.1001A>G
MANE Select: NM_001725
dbSNP: rs775959420
Type: single nucleotide variant
Location: chr20:38326272 (GRCh38)
Gene constraint: LOEUF 1.011 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.70 · 2 PDB
Residue 334: 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-lys334arg (accessed [today's date]).

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