Is BPIFC p.Trp16Arg (c.46T>C) pathogenic?

BPIFC p.Trp16Arg (c.46T>C) is classified Uncertain significance in BPIFC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.4949); Ultra-rare (popmax 0.0497%, sas).

How common is BPIFC p.Trp16Arg (c.46T>C) in the general population?

BPIFC p.Trp16Arg (c.46T>C) is ultra-rare (popmax 0.0497%, sas) (gnomAD).

What do computational predictors say about BPIFC p.Trp16Arg (c.46T>C)?

AlphaMissense predicts ambiguous (score 0.4949) — an in-silico prediction, not a clinical call.

BPIFC p.Trp16Arg

c.46T>C · VCV3992506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4949 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0497%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4949	ambiguous
REVEL	0.272	benign-leaning
SaProt	LLR -8.38	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 43 kb · p 0.43 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0497% South Asian · 45/90,460 alleles

Filtering AF 0.0381% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0341%

Overall 0.00298% 48/1,610,616 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0497%	2,010
Remaining individualsnot grpmax-eligible	0.00481%	20,794

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: BPIFC
Protein: p.Trp16Arg
Coding: c.46T>C
MANE Select: NM_174932
Type: single nucleotide variant
Location: chr22:32457341 (GRCh38)
Gene constraint: LOEUF 1.253 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.60

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

Similar variants

BPIFC p.Ala184Val Uncertain significance ★ ⚠ same type
BPIFC p.Ala204Ser Uncertain significance ★ ⚠ same type
BPIFC p.Ala209Val Uncertain significance ★ ⚠ same type
BPIFC p.Ala96Ser Uncertain significance ★ ⚠ same type
BPIFC p.Ala96Val Uncertain significance ★ ⚠ same type
BPIFC p.Arg273Cys Uncertain significance ★ ⚠ same type
BPIFC p.Arg326Gln Uncertain significance ★ ⚠ same type
BPIFC p.Arg326Trp 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/bpifc-p-trp16arg (accessed [today's date]).

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