Is BPNT2 p.Pro126Arg (c.377C>G) pathogenic?

BPNT2 p.Pro126Arg (c.377C>G) is classified Uncertain significance in BPNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: ambiguous (0.4013); Very rare (popmax 0.00167%, amr).

How common is BPNT2 p.Pro126Arg (c.377C>G) in the general population?

BPNT2 p.Pro126Arg (c.377C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about BPNT2 p.Pro126Arg (c.377C>G)?

AlphaMissense predicts ambiguous (score 0.4013) — an in-silico prediction, not a clinical call.

BPNT2 p.Pro126Arg

c.377C>G · rs1202905686 · VCV1906634

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4013 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4013	ambiguous
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -12.94	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.51 · regional, not allelic
Overall
CADD	29.6	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 0.00167% Admixed American · 1/59,882 alleles

Overall 6.9e-05% 1/1,448,296 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: BPNT2
Protein: p.Pro126Arg
Coding: c.377C>G
MANE Select: NM_017813
dbSNP: rs1202905686
Type: single nucleotide variant
Location: chr8:56993209 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.79 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.55

Full BPNT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BPNT2 p.Arg187Ter Pathogenic ★★ same type
BPNT2 c.-155C>G Uncertain significance ★★ same type
BPNT2 c.*4264G>A Uncertain significance ★★ same type
BPNT2 c.*5193A>G Uncertain significance ★★ same type
BPNT2 p.Ala218Ser Uncertain significance ★★ ⚠ same type
BPNT2 p.Arg187Gln Uncertain significance ★★ ⚠ same type
BPNT2 p.Arg243Cys Uncertain significance ★★ ⚠ same type
BPNT2 p.Arg243His 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/bpnt2-p-pro126arg (accessed [today's date]).

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