Is BPIFA1 p.Val253Phe (c.757G>T) pathogenic?

BPIFA1 p.Val253Phe (c.757G>T) is classified Uncertain significance in BPIFA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-04). AlphaMissense: likely benign (0.2037); Very rare (popmax 0.00167%, amr).

How common is BPIFA1 p.Val253Phe (c.757G>T) in the general population?

BPIFA1 p.Val253Phe (c.757G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about BPIFA1 p.Val253Phe (c.757G>T)?

AlphaMissense predicts likely benign (score 0.2037) — an in-silico prediction, not a clinical call.

BPIFA1 p.Val253Phe

c.757G>T · VCV3825140

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2037 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2037	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.84	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 -1.5, phastCons 0.4
Regional constraint	o/e 1.13	unconstrained · MANE · 4,812 bp · p 0.021 · regional, not allelic
Overall
CADD	16.52	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 0.00167% Admixed American · 1/60,022 alleles

Overall 6.84e-05% 1/1,461,820 alleles · very rare

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: BPIFA1
Protein: p.Val253Phe
Coding: c.757G>T
MANE Select: NM_130852
Type: single nucleotide variant
Location: chr20:33242513 (GRCh38)
Gene constraint: LOEUF 1.355 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.06 · 7 PDB

Full BPIFA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BPIFA1 p.Gln188Lys Benign ★★ same type
BPIFA1 p.Asp112Glu Uncertain significance ★ ⚠ same type
BPIFA1 p.Gln20Pro Uncertain significance ★ ⚠ same type
BPIFA1 p.Gln30Glu Uncertain significance ★ ⚠ same type
BPIFA1 p.Glu171Lys Uncertain significance ★ ⚠ same type
BPIFA1 p.Gly196Ser Uncertain significance ★ ⚠ same type
BPIFA1 p.Gly249Arg Uncertain significance ★ ⚠ same type
BPIFA1 p.Gly66Asp 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/bpifa1-p-val253phe (accessed [today's date]).

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