SLC9A3

Chr 5AR

solute carrier family 9 member A3

Also known as: DIAR8, NHE-3, NHE3

NCBI Gene: 6550ENSG00000066230UniProt: P48764OMIM: 182307

This sodium/hydrogen exchanger functions as a plasma membrane antiporter that exchanges intracellular H+ ions for extracellular Na+ in 1:1 stoichiometry, serving as the major apical Na+/H+ exchanger in kidney and intestine for sodium absorption and pH homeostasis. Mutations cause congenital secretory sodium diarrhea with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismARLOEUF 0.311 OMIM phenotype
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
39 unique Pathogenic / Likely Pathogenic· 129 VUS of 500 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
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
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
LoF OE0.16 (0.09–0.31)
0≤0.351.4
Missense OE0.69 (0.64–0.76)
0≤0.61.4
Synonymous OE1.17
0≤1.21.6
LoF obs/exp: 6 / 38.2Missense obs/exp: 365 / 525.7Syn Z: -2.05
DN
0.6647th %ile
GOF
0.76top 25%
LOF
0.50top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF31% of P/LP variants are LoF · LOEUF 0.31
GOFprediction above median
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35
Likely Pathogenic4
VUS129
Likely Benign308
Benign2
Conflicting3
35
Pathogenic
4
Likely Pathogenic
129
VUS
308
Likely Benign
2
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
0
26
0
35
Likely Pathogenic
3
1
0
0
4
VUS
2
110
17
0
129
Likely Benign
0
4
114
190
308
Benign
0
0
2
0
2
Conflicting
—3
Total14115159190481

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients