Is BSND p.Arg8Gln (c.23G>A) pathogenic?

BSND p.Arg8Gln (c.23G>A) is classified Conflicting classifications of pathogenicity in BSND (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-05-09). AlphaMissense: ambiguous (0.5299); Ultra-rare (popmax 0.0527%, sas); Associated with Monogenic hearing loss.

What condition is associated with BSND p.Arg8Gln (c.23G>A)?

BSND p.Arg8Gln (c.23G>A) is associated with Monogenic hearing loss, Bartter disease type 4A, Bartter syndrome (ClinVar).

How common is BSND p.Arg8Gln (c.23G>A) in the general population?

BSND p.Arg8Gln (c.23G>A) is ultra-rare (popmax 0.0527%, sas) (gnomAD).

What do computational predictors say about BSND p.Arg8Gln (c.23G>A)?

AlphaMissense predicts ambiguous (score 0.5299) — an in-silico prediction, not a clinical call.

BSND p.Arg8Gln

c.23G>A · rs74315288 · VCV2202510

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.5299 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0527%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Monogenic hearing loss

Computational evidence

Protein change
AlphaMissense	0.5299	ambiguous
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -8.56	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 9,438 bp · p 0.065 · 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 0.0527% South Asian · 48/91,092 alleles

Filtering AF 0.0408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.00905% 146/1,614,012 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0527%	1,898
Remaining individualsnot grpmax-eligible	0.024%	4,166
East Asian	0.00891%	11,220
European (non-Finnish)	0.00619%	16,165
Finnishnot grpmax-eligible	0.00469%	21,331
Admixed American	0.00333%	30,000
African / African-American	0.00133%	74,926

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: BSND
Protein: p.Arg8Gln
Coding: c.23G>A
MANE Select: NM_057176
dbSNP: rs74315288
Type: single nucleotide variant
Location: chr1:54999209 (GRCh38)
Gene constraint: LOEUF 1.03 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 53.80
Residue 8: a UniProt-annotated variant site (in barts4a); a UniProt-annotated variant site (in barts4a; fails to activate clcnka and clcnkb channels); a UniProt-annotated variant site (in barts4a; fails to activate clcnka and clcnkb channels; loss of channel conductance); the 'regulates channel membrane trafficking and ion conductance' region

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

Disease context

Monogenic hearing loss

Also linked: Bartter disease type 4A Bartter syndrome Bartter syndrome type 4

Similar variants

BSND p.Arg8Trp Pathogenic/Likely pathogenic ★★ same residue
BSND p.Arg8Leu Pathogenic same residue
BSND p.Arg8Gly Pathogenic ★ same residue
BSND p.Arg8= Likely benign ★ same residue
BSND c.178-2A>C Likely pathogenic ★★ same condition
BSND c.272+1G>T Pathogenic/Likely pathogenic ★★ same condition
BSND p.Gln95Ter Pathogenic/Likely pathogenic ★★ same condition
BSND p.Glu148Ter Pathogenic/Likely pathogenic ★★ same condition

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/bsnd-p-arg8gln (accessed [today's date]).

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