Is CLCNKB p.Pro563= (c.1689A>G) pathogenic?

CLCNKB p.Pro563= (c.1689A>G) is classified Likely benign in CLCNKB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-16). Ultra-rare (popmax 0.09%, amr); Associated with Bartter disease type 3.

What condition is associated with CLCNKB p.Pro563= (c.1689A>G)?

CLCNKB p.Pro563= (c.1689A>G) is associated with Bartter disease type 3, Bartter disease type 4B (ClinVar).

How common is CLCNKB p.Pro563= (c.1689A>G) in the general population?

CLCNKB p.Pro563= (c.1689A>G) is ultra-rare (popmax 0.09%, amr) (gnomAD).

How is Bartter syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CLCNKB p.Pro563=

c.1689A>G · rs185493054 · VCV717133

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.09%, amr)

Conditions

Bartter disease type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -4
Overall
CADD	0.009	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.09% Admixed American · 54/60,008 alleles

Filtering AF 0.0708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0639%

Overall 0.0129% 208/1,613,902 alleles · ultra-rare exomes 169/1,461,702 · genomes 39/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.09%	1,111
Finnishnot grpmax-eligible	0.072%	1,389
East Asian	0.0535%	1,870
South Asian	0.0275%	3,643
Remaining individualsnot grpmax-eligible	0.0112%	8,929
European (non-Finnish)	0.00415%	24,081
African / African-American	0.004%	24,999

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: CLCNKB
Protein: p.Pro563=
Coding: c.1689A>G
MANE Select: NM_000085
dbSNP: rs185493054
Type: single nucleotide variant
Location: chr1:16053705 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.16
Residue 563: the cbs 1 domain

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

Disease context

Bartter disease type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bartter disease type 4B

For Bartter syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

CLCNKB c.968+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLCNKB p.Ala204Thr Pathogenic/Likely pathogenic ★★ same condition
CLCNKB p.Arg304Ter Pathogenic/Likely pathogenic ★★ same condition
CLCNKB p.Arg438His Pathogenic ★★ same condition
CLCNKB p.Arg595Ter Pathogenic ★★ same condition
CLCNKB p.Arg76Ter Pathogenic ★★ same condition
CLCNKB p.Glu225Ter Pathogenic ★★ same condition
CLCNKB p.Gly424Arg 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/clcnkb-p-pro563 (accessed [today's date]).

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