Is BPIFA2 p.Pro138Leu (c.413C>T) pathogenic?

BPIFA2 p.Pro138Leu (c.413C>T) is classified Uncertain significance in BPIFA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-04). AlphaMissense: likely benign (0.288); Ultra-rare (popmax 0.0167%, amr).

How common is BPIFA2 p.Pro138Leu (c.413C>T) in the general population?

BPIFA2 p.Pro138Leu (c.413C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about BPIFA2 p.Pro138Leu (c.413C>T)?

AlphaMissense predicts likely benign (score 0.288) — an in-silico prediction, not a clinical call.

BPIFA2 p.Pro138Leu

c.413C>T · rs750897300 · VCV2235936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.288 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.288	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -6.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.027	GERP 0.76, phastCons 0.008
Regional constraint	o/e 1.01	unconstrained · MANE · 11 kb · p 0.91 · regional, not allelic
Overall
CADD	22.2	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 0.0167% Admixed American · 10/59,900 alleles

Filtering AF 0.00901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00682%

Overall 0.000744% 12/1,613,206 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,990
Remaining individualsnot grpmax-eligible	0.0032%	31,234

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: BPIFA2
Protein: p.Pro138Leu
Coding: c.413C>T
MANE Select: NM_080574
dbSNP: rs750897300
Type: single nucleotide variant
Location: chr20:33175409 (GRCh38)
Gene constraint: LOEUF 1.122 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.37

Full BPIFA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BPIFA2 p.Gly101= Benign ★★ same type
BPIFA2 p.Ala131Val Uncertain significance ★ ⚠ same type
BPIFA2 p.Ala155Pro Uncertain significance ★ ⚠ same type
BPIFA2 p.Ala155Thr Uncertain significance ★ ⚠ same type
BPIFA2 p.Asp118Asn Uncertain significance ★ ⚠ same type
BPIFA2 p.Asp187Glu Uncertain significance ★ ⚠ same type
BPIFA2 p.Asp28Glu Uncertain significance ★ ⚠ same type
BPIFA2 p.Gln3Pro 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/bpifa2-p-pro138leu (accessed [today's date]).

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