Is BPIFA3 p.His141Pro (c.422A>C) pathogenic?

BPIFA3 p.His141Pro (c.422A>C) is classified Uncertain significance in BPIFA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely benign (0.3153); Very rare (popmax 0.000254%, nfe).

How common is BPIFA3 p.His141Pro (c.422A>C) in the general population?

BPIFA3 p.His141Pro (c.422A>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about BPIFA3 p.His141Pro (c.422A>C)?

AlphaMissense predicts likely benign (score 0.3153) — an in-silico prediction, not a clinical call.

BPIFA3 p.His141Pro

c.422A>C · VCV3992446

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3153 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3153	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -11.18	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -2.6
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.51 · regional, not allelic
Overall
CADD	0.656	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 0.000254% European (non-Finnish) · 3/1,180,028 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,880 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.His141Pro
Coding: c.422A>C
MANE Select: NM_178466
Type: single nucleotide variant
Location: chr20:33225133 (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.His141Leu Uncertain significance ★ ⚠ same residue
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

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-his141pro (accessed [today's date]).

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