Is BPIFA2 p.Ile158Thr (c.473T>C) pathogenic?

BPIFA2 p.Ile158Thr (c.473T>C) is classified Uncertain significance in BPIFA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: likely benign (0.2348); Very rare (popmax 0.00439%, sas).

How common is BPIFA2 p.Ile158Thr (c.473T>C) in the general population?

BPIFA2 p.Ile158Thr (c.473T>C) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about BPIFA2 p.Ile158Thr (c.473T>C)?

AlphaMissense predicts likely benign (score 0.2348) — an in-silico prediction, not a clinical call.

BPIFA2 p.Ile158Thr

c.473T>C · rs1375640196 · VCV2264350

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2348 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2348	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -7.68	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 3.2	GERP 0.72, phastCons 0.35
Regional constraint	o/e 1.01	unconstrained · MANE · 11 kb · p 0.91 · regional, not allelic
Overall
CADD	20.4	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 0.00439% South Asian · 4/91,058 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000342% 5/1,461,782 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,765
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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: BPIFA2
Protein: p.Ile158Thr
Coding: c.473T>C
MANE Select: NM_080574
dbSNP: rs1375640196
Type: single nucleotide variant
Location: chr20:33175469 (GRCh38)
Gene constraint: LOEUF 1.122 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.37

Full BPIFA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BPIFA2 p.Ile158Val Likely benign ★ same residue
BPIFA2 p.Gly101= Benign ★★ same type
BPIFA2 p.Ala131Val Uncertain significance ★ ⚠ same type
BPIFA2 p.Ala155Pro Uncertain significance ★ ⚠ same type
BPIFA2 p.Ala155Thr Uncertain significance ★ ⚠ same type
BPIFA2 p.Asp118Asn Uncertain significance ★ ⚠ same type
BPIFA2 p.Asp187Glu Uncertain significance ★ ⚠ same type
BPIFA2 p.Asp28Glu 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/bpifa2-p-ile158thr (accessed [today's date]).

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