Is SLC12A3 p.Pro656= (c.1968G>A) pathogenic?

SLC12A3 p.Pro656= (c.1968G>A) is classified Conflicting classifications of pathogenicity in SLC12A3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-04-01). Ultra-rare (popmax 0.0667%, amr); Associated with Gitelman syndrome.

What condition is associated with SLC12A3 p.Pro656= (c.1968G>A)?

SLC12A3 p.Pro656= (c.1968G>A) is associated with Gitelman syndrome (ClinVar).

How common is SLC12A3 p.Pro656= (c.1968G>A) in the general population?

SLC12A3 p.Pro656= (c.1968G>A) is ultra-rare (popmax 0.0667%, amr) (gnomAD).

How is Gitelman syndrome inherited?

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

SLC12A3 p.Pro656=

c.1968G>A · rs150378634 · VCV319910

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, amr)

Conditions

Gitelman syndrome

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 -15	GERP -5.4
Overall
CADD	0.686	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0667% Admixed American · 40/60,006 alleles

Filtering AF 0.0503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.0118% 190/1,613,946 alleles · ultra-rare exomes 170/1,461,774 · genomes 20/152,172 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0667%	1,500
African / African-American	0.0107%	9,366
European (non-Finnish)	0.0106%	9,440
South Asian	0.00878%	11,386
Remaining individualsnot grpmax-eligible	0.008%	12,497
Finnishnot grpmax-eligible	0.00469%	21,312
East Asian	0.00223%	44,868

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: SLC12A3
Protein: p.Pro656=
Coding: c.1968G>A
MANE Select: NM_001126108
dbSNP: rs150378634
Type: single nucleotide variant
Location: chr16:56886406 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 12 PDB
Residue 656: an α-helix

Full SLC12A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Gitelman syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Gitelman syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

SLC12A3 p.Pro656Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SLC12A3 p.Pro656Arg Uncertain significance ★ ⚠ same residue
SLC12A3 c.1095+1G>C Pathogenic/Likely pathogenic ★★ same condition
SLC12A3 c.1095+4A>G Pathogenic/Likely pathogenic ★★ same condition
SLC12A3 c.1096-1G>A Pathogenic/Likely pathogenic ★★ same condition
SLC12A3 c.1096-2A>G Pathogenic/Likely pathogenic ★★ same condition
SLC12A3 c.1180+1G>T Pathogenic ★★ same condition
SLC12A3 c.1180+2T>C 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/slc12a3-p-pro656 (accessed [today's date]).

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