Is BSND p.Leu18Val (c.52C>G) pathogenic?

BSND p.Leu18Val (c.52C>G) is classified Uncertain significance in BSND (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: ambiguous (0.455); Ultra-rare (popmax 0.0626%, sas); Associated with Bartter disease type 4A.

What condition is associated with BSND p.Leu18Val (c.52C>G)?

BSND p.Leu18Val (c.52C>G) is associated with Bartter disease type 4A (ClinVar).

How common is BSND p.Leu18Val (c.52C>G) in the general population?

BSND p.Leu18Val (c.52C>G) is ultra-rare (popmax 0.0626%, sas) (gnomAD).

What do computational predictors say about BSND p.Leu18Val (c.52C>G)?

AlphaMissense predicts ambiguous (score 0.455) — an in-silico prediction, not a clinical call.

BSND p.Leu18Val

c.52C>G · rs754403589 · VCV634810

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.455 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0626%, sas)

Conditions

Bartter disease type 4A

Computational evidence

Protein change
AlphaMissense	0.455	ambiguous
REVEL	0.331	indeterminate
SaProt	LLR -6.28	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 9,438 bp · p 0.065 · regional, not allelic
Overall
CADD	25.1	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 0.0626% South Asian · 57/91,094 alleles

Filtering AF 0.0496% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0449%

Overall 0.00353% 57/1,614,034 alleles · ultra-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: BSND
Protein: p.Leu18Val
Coding: c.52C>G
MANE Select: NM_057176
dbSNP: rs754403589
Type: single nucleotide variant
Location: chr1:54999238 (GRCh38)
Gene constraint: LOEUF 1.03 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 53.80
Residue 18: a UniProt-annotated variant site (in barts4a); 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

Bartter disease type 4A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BSND c.272+1G>T Pathogenic/Likely pathogenic ★★ same condition
BSND p.Arg8Trp Pathogenic/Likely pathogenic ★★ same condition
BSND p.Glu4Ter Pathogenic ★★ same condition
BSND p.Glu88Ter Pathogenic/Likely pathogenic ★★ same condition
BSND p.Gly10Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
BSND p.Gly47Arg Pathogenic/Likely pathogenic ★★ same condition
BSND p.Ile12Thr Pathogenic ★★ same condition
BSND p.Met1Ile 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-leu18val (accessed [today's date]).

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