Is BPIFA3 p.Leu9Phe (c.25C>T) pathogenic?

BPIFA3 p.Leu9Phe (c.25C>T) is classified Uncertain significance in BPIFA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-26). AlphaMissense: likely benign (0.1017); Very rare (popmax 0.00102%, nfe).

How common is BPIFA3 p.Leu9Phe (c.25C>T) in the general population?

BPIFA3 p.Leu9Phe (c.25C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about BPIFA3 p.Leu9Phe (c.25C>T)?

AlphaMissense predicts likely benign (score 0.1017) — an in-silico prediction, not a clinical call.

BPIFA3 p.Leu9Phe

c.25C>T · rs368746864 · VCV3134816

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1017	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -7.77	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 1.2	GERP -1.7, phastCons 0.63
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.51 · regional, not allelic
Overall
CADD	16.21	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 0.00102% European (non-Finnish) · 12/1,180,020 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000805% 13/1,614,070 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)grpmax	0.00102%	98,335

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: BPIFA3
Protein: p.Leu9Phe
Coding: c.25C>T
MANE Select: NM_178466
dbSNP: rs368746864
Type: single nucleotide variant
Location: chr20:33217561 (GRCh38)
Gene constraint: LOEUF 1.511 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.36

Full BPIFA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BPIFA3 p.Ala140Val Uncertain significance ★ ⚠ same type
BPIFA3 p.Ala20Ser Uncertain significance ★ ⚠ same type
BPIFA3 p.Ala53Thr Uncertain significance ★ ⚠ same type
BPIFA3 p.Ala73Thr Uncertain significance ★ ⚠ same type
BPIFA3 p.Asn67Ser Uncertain significance ★ ⚠ same type
BPIFA3 p.Asp132His Uncertain significance ★ ⚠ same type
BPIFA3 p.Gln46Pro Uncertain significance ★ ⚠ same type
BPIFA3 p.Gln87Arg 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/bpifa3-p-leu9phe (accessed [today's date]).

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