Is BPNT2 p.Arg229His (c.686G>A) pathogenic?

BPNT2 p.Arg229His (c.686G>A) is classified Uncertain significance in BPNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-02). AlphaMissense: ambiguous (0.3851); Ultra-rare (popmax 0.012%, afr).

How common is BPNT2 p.Arg229His (c.686G>A) in the general population?

BPNT2 p.Arg229His (c.686G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about BPNT2 p.Arg229His (c.686G>A)?

AlphaMissense predicts ambiguous (score 0.3851) — an in-silico prediction, not a clinical call.

BPNT2 p.Arg229His

c.686G>A · rs758965196 · VCV3134883

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3851 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3851	ambiguous
REVEL	0.225	benign-leaning
SaProt	LLR -6.49	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.51 · regional, not allelic
Overall
CADD	28.9	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 0.012% African / African-American · 9/74,918 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00192% 31/1,613,824 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,324
East Asian	0.00223%	44,866
European (non-Finnish)	0.00178%	56,184

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.Arg229His
Coding: c.686G>A
MANE Select: NM_017813
dbSNP: rs758965196
Type: single nucleotide variant
Location: chr8:56966313 (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.Arg229= Uncertain significance ★ same residue
BPNT2 p.Arg229Cys Uncertain significance ★ ⚠ same residue
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

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-arg229his (accessed [today's date]).

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