SLC9A3

Chr 5AR

solute carrier family 9 member A3

NCBI Gene: 6550ENSG00000066230UniProt: P48764

Plasma membrane Na(+)/H(+) antiporter (PubMed:18829453, PubMed:26358773, PubMed:35613257). Exchanges intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry, playing a key role in salt and fluid absorption and pH homeostasis (By similarity). Major apical Na(+)/H(+) exchanger in kidney and intestine playing an important role in renal and intestine Na(+) absorption and blood pressure regulation (PubMed:24622516, PubMed:26358773)

Primary Disease Associations & Inheritance

Diarrhea 8, secretory sodium, congenitalMIM #616868
AR
581
ClinVar variants
37
Pathogenic / LP
0.98
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SLC9A3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
37 Pathogenic / Likely Pathogenic· 152 VUS of 581 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.31LOEUF
pLI 0.978
Z-score 4.83
OE 0.16 (0.09–0.31)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.49Z-score
OE missense 0.69 (0.64–0.76)
365 obs / 525.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.16 (0.09–0.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.69 (0.64–0.76)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.17
0≤1.21.6
LoF obs/exp: 6 / 38.2Missense obs/exp: 365 / 525.7Syn Z: -2.05

ClinVar Variant Classifications

581 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic4
VUS152
Likely Benign377
Benign12
Conflicting3
33
Pathogenic
4
Likely Pathogenic
152
VUS
377
Likely Benign
12
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
0
26
0
33
Likely Pathogenic
3
1
0
0
4
VUS
2
129
21
0
152
Likely Benign
0
6
139
232
377
Benign
0
2
4
6
12
Conflicting
—3
Total12138190238581

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SLC9A3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Diarrhea 8, secretory sodium, congenital

MIM #616868

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The role of SLC9A3 in Taiwanese patients with congenital bilateral absence of vas deferens (CBAVD).
Chiang HS et al.·J Formos Med Assoc
2019Review
Insight into SLC9A3 deficiency-mediated micturition dysfunction caused by electrolyte imbalance.
Chen KC et al.·Biomed Pharmacother
2023
Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice.
Wang YY et al.·PLoS Genet
2017
Further delineation of SLC9A3-related congenital sodium diarrhea.
Bogdanic E et al.·Mol Genet Genomic Med
2022Case report
SLC9A3 Affects Vas Deferens Development and Associates with Taiwanese Congenital Bilateral Absence of the Vas Deferens.
Wu YN et al.·Biomed Res Int
2019
Small Intestinal Phosphate Absorption: Novel Therapeutic Implications.
Yee J et al.·Am J Nephrol
2021Review
Interaction among variants in the SLC gene family (SLC6A14, SLC26A9, SLC11A1, and SLC9A3) and CFTR mutations with clinical markers of cystic fibrosis.
Pereira SVN et al.·Pediatr Pulmonol
2018
Congenital Sodium Diarrhea: A Form of Intractable Diarrhea, With a Link to Inflammatory Bowel Disease.
Janecke AR et al.·J Pediatr Gastroenterol Nutr
2016Review
Comprehensive exome profiling identifies ARHGEF12 mutation as a driver in gastric cancer with ovarian metastasis.
Zhang M et al.·Theranostics
2025
Association of clinical severity of cystic fibrosis with variants in the SLC gene family (SLC6A14, SLC26A9, SLC11A1 and SLC9A3).
Pereira SV et al.·Gene
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools