Is BPNT2 p.Arg243His (c.728G>A) pathogenic?

BPNT2 p.Arg243His (c.728G>A) is classified Uncertain significance in BPNT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-25). AlphaMissense: ambiguous (0.4471); Ultra-rare (popmax 0.0156%, eas).

How common is BPNT2 p.Arg243His (c.728G>A) in the general population?

BPNT2 p.Arg243His (c.728G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about BPNT2 p.Arg243His (c.728G>A)?

AlphaMissense predicts ambiguous (score 0.4471) — an in-silico prediction, not a clinical call.

BPNT2 p.Arg243His

c.728G>A · rs148507660 · VCV1011336

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4471 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4471	ambiguous
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -12.73	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.32 · evaluated, not missing
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	33.0	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 0.0156% East Asian · 7/44,852 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00105% 17/1,613,930 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.11%	910
East Asiangrpmax	0.0156%	6,407
Remaining individualsnot grpmax-eligible	0.0016%	62,506
African / African-American	0.00133%	75,036
European (non-Finnish)	0.000593%	168,548

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg243His
Coding: c.728G>A
MANE Select: NM_017813
dbSNP: rs148507660
Type: single nucleotide variant
Location: chr8:56966271 (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.Arg243Cys 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
BPNT2 p.Asp278Gly 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-arg243his (accessed [today's date]).

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