Is BPI p.Pro221Thr (c.661C>A) pathogenic?

BPI p.Pro221Thr (c.661C>A) is classified Uncertain significance in BPI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-13). AlphaMissense: likely benign (0.2175); Rare (popmax 0.204%, afr).

How common is BPI p.Pro221Thr (c.661C>A) in the general population?

BPI p.Pro221Thr (c.661C>A) is rare (popmax 0.204%, afr) (gnomAD).

What do computational predictors say about BPI p.Pro221Thr (c.661C>A)?

AlphaMissense predicts likely benign (score 0.2175) — an in-silico prediction, not a clinical call.

BPI p.Pro221Thr

c.661C>A · rs111327200 · VCV2339275

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2175 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.204%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2175	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -11.62	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 33 kb · p 0.094 · regional, not allelic
Overall
CADD	21.2	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 P225T vs ClinVar P221T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.204% African / African-American · 153/74,978 alleles

Filtering AF 0.178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.168%

Overall 0.0204% 329/1,612,788 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.204%	490
South Asian	0.145%	690
Middle Eastern	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.032%	3,123
Admixed American	0.00333%	30,005
European (non-Finnish)	0.00136%	73,676

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.Pro221Thr
Coding: c.661C>A
MANE Select: NM_001725
dbSNP: rs111327200
Type: single nucleotide variant
Location: chr20:38318473 (GRCh38)
Gene constraint: LOEUF 1.011 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.70 · 2 PDB
Residue 221: the 'n-terminal barrel' region; an α-helix

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-pro221thr (accessed [today's date]).

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