Is BPIFA3 p.Pro253Ser (c.757C>T) pathogenic?

BPIFA3 p.Pro253Ser (c.757C>T) is classified Likely benign in BPIFA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.071); Very rare (popmax 8.48e-05%, nfe).

How common is BPIFA3 p.Pro253Ser (c.757C>T) in the general population?

BPIFA3 p.Pro253Ser (c.757C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about BPIFA3 p.Pro253Ser (c.757C>T)?

AlphaMissense predicts likely benign (score 0.071) — an in-silico prediction, not a clinical call.

BPIFA3 p.Pro253Ser

c.757C>T · VCV4214877

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.071 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.071	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -5.32	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 0.16	GERP -1.1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.51 · regional, not allelic
Overall
CADD	14.85	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 8.48e-05% European (non-Finnish) · 1/1,179,736 alleles

Overall 6.84e-05% 1/1,461,578 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: BPIFA3
Protein: p.Pro253Ser
Coding: c.757C>T
MANE Select: NM_178466
Type: single nucleotide variant
Location: chr20:33227609 (GRCh38)
Gene constraint: LOEUF 1.511 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.36
Residue 253: the 'disordered' region

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-pro253ser (accessed [today's date]).

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