Is BPIFB3 p.Ala28Ser (c.82G>T) pathogenic?

BPIFB3 p.Ala28Ser (c.82G>T) is classified Uncertain significance in BPIFB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely benign (0.261); Ultra-rare (popmax 0.0667%, amr).

How common is BPIFB3 p.Ala28Ser (c.82G>T) in the general population?

BPIFB3 p.Ala28Ser (c.82G>T) is ultra-rare (popmax 0.0667%, amr) (gnomAD).

What do computational predictors say about BPIFB3 p.Ala28Ser (c.82G>T)?

AlphaMissense predicts likely benign (score 0.261) — an in-silico prediction, not a clinical call.

BPIFB3 p.Ala28Ser

c.82G>T · rs138919082 · VCV2259461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.261 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.261	likely benign
REVEL	0.192	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 18 kb · p 0.14 · regional, not allelic
Overall
CADD	22.0	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 A32S vs ClinVar A28S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0667% Admixed American · 40/60,008 alleles

Filtering AF 0.0503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.0151% 244/1,613,640 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0667%	1,500
Finnishnot grpmax-eligible	0.0425%	2,353
Remaining individualsnot grpmax-eligible	0.016%	6,251
European (non-Finnish)	0.0137%	7,284
South Asian	0.00439%	22,770
African / African-American	0.00133%	75,038

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: BPIFB3
Protein: p.Ala28Ser
Coding: c.82G>T
MANE Select: NM_001376932
dbSNP: rs138919082
Type: single nucleotide variant
Location: chr20:33055517 (GRCh38)
Gene constraint: LOEUF 1.158 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.71

Full BPIFB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BPIFB3 p.Ala28Thr Uncertain significance ★ ⚠ same residue
BPIFB3 p.Ala134Ser Uncertain significance ★ ⚠ same type
BPIFB3 p.Ala134Val Uncertain significance ★ ⚠ same type
BPIFB3 p.Ala135Val Uncertain significance ★ ⚠ same type
BPIFB3 p.Ala144Ser Uncertain significance ★ ⚠ same type
BPIFB3 p.Ala211Val Uncertain significance ★ ⚠ same type
BPIFB3 p.Ala317Thr Uncertain significance ★ ⚠ same type
BPIFB3 p.Ala352Asp 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/bpifb3-p-ala28ser (accessed [today's date]).

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