Is BPIFB2 p.Ile397Phe (c.1189A>T) pathogenic?

BPIFB2 p.Ile397Phe (c.1189A>T) is classified Uncertain significance in BPIFB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.124); Ultra-rare (popmax 0.0575%, nfe).

How common is BPIFB2 p.Ile397Phe (c.1189A>T) in the general population?

BPIFB2 p.Ile397Phe (c.1189A>T) is ultra-rare (popmax 0.0575%, nfe) (gnomAD).

What do computational predictors say about BPIFB2 p.Ile397Phe (c.1189A>T)?

AlphaMissense predicts likely benign (score 0.124) — an in-silico prediction, not a clinical call.

BPIFB2 p.Ile397Phe

c.1189A>T · rs148403687 · VCV2342054

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.124 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0575%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.124	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -7.72	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 0.3	GERP -3.8
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.62 · regional, not allelic
Overall
CADD	5.852	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0575% European (non-Finnish) · 676/1,176,516 alleles

Filtering AF 0.0538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0524%

Overall 0.0456% 733/1,608,298 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0575%	1,740
Admixed American	0.0453%	2,207
Remaining individualsnot grpmax-eligible	0.0353%	2,830
Middle Eastern	0.0331%	3,017
African / African-American	0.00667%	14,984
South Asian	0.00111%	90,104

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: BPIFB2
Protein: p.Ile397Phe
Coding: c.1189A>T
MANE Select: NM_025227
dbSNP: rs148403687
Type: single nucleotide variant
Location: chr20:33020582 (GRCh38)
Gene constraint: LOEUF 0.959 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.04

Full BPIFB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BPIFB2 p.Ala104Ser Uncertain significance ★ ⚠ same type
BPIFB2 p.Ala104Thr Uncertain significance ★ ⚠ same type
BPIFB2 p.Ala144Thr Uncertain significance ★ ⚠ same type
BPIFB2 p.Ala267Val Uncertain significance ★ ⚠ same type
BPIFB2 p.Ala274Thr Uncertain significance ★ ⚠ same type
BPIFB2 p.Ala420Val Uncertain significance ★ ⚠ same type
BPIFB2 p.Ala48Ser Uncertain significance ★ ⚠ same type
BPIFB2 p.Ala63Glu Uncertain significance ★ ⚠ 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/bpifb2-p-ile397phe (accessed [today's date]).

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