SLC9A1

Chr 1AR

solute carrier family 9 member A1

Also known as: APNH, LIKNS, NHE-1, NHE1, PPP1R143

NCBI Gene: 6548ENSG00000090020UniProt: P19634

This gene encodes a Na+/H+ antiporter that is a member of the solute carrier family 9. The encoded protein is a plasma membrane transporter that is expressed in the kidney and intestine. This protein plays a central role in regulating pH homeostasis, cell migration and cell volume. This protein may also be involved in tumor growth. [provided by RefSeq, Sep 2011]

Primary Disease Associations & Inheritance

Lichtenstein-Knorr syndromeMIM #616291
AR
0
Active trials
14
Pathogenic / LP
266
ClinVar variants
9
Pubs (1 yr)
3.6
Missense Z· constrained
0.38
LOEUF
Clinical Summary— SLC9A1
🧬
Gene-Disease Validity (ClinGen)
Lichtenstein-Knorr syndrome · ARModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.79) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 133 VUS of 266 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint
0.38LOEUF
pLI 0.790
Z-score 4.22
OE 0.19 (0.10–0.38)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
3.55Z-score
OE missense 0.56 (0.51–0.62)
292 obs / 519.8 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.19 (0.10–0.38)
0≤0.351.4
Missense OE0.56 (0.51–0.62)
0≤0.61.4
Synonymous OE0.86
0≤1.21.6
LoF obs/exp: 6 / 31.6Missense obs/exp: 292 / 519.8Syn Z: 1.66
GOFDNLOF
DN
0.6453th %ile
GOF
0.74top 25%
LOF
0.4627th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction above median
LOF21% of P/LP variants are LoF · LOEUF 0.38

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

266 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic3
VUS133
Likely Benign103
Benign12
Conflicting4
11
Pathogenic
3
Likely Pathogenic
133
VUS
103
Likely Benign
12
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
9
0
11
Likely Pathogenic
1
2
0
0
3
VUS
4
118
11
0
133
Likely Benign
0
1
25
77
103
Benign
0
1
6
5
12
Conflicting
—4
Total71225182266

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

View in ClinVar →

SLC9A1 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
High-Salt-Diet (HSD) aggravates the progression of Inflammatory Bowel Disease (IBD) via regulating epithelial necroptosis
Qi J et al.·Mol Biomed
2023
Identification of co-diagnostic effect genes for aortic dissection and metabolic syndrome by multiple machine learning algorithms
Zhang Y et al.·Sci Rep
2023
Osmotic stress activates RIPK3/MLKL-mediated necroptosis by increasing cytosolic pH through a plasma membrane Na+/H+ exchanger.
Zhang W et al.·Sci Signal
2022
Employing the sustained-release properties of poly(lactic-co-glycolic acid) nanoparticles to reveal a novel mechanism of sodium-hydrogen exchanger 1 in neuropathic pain.
Wu J et al.·Transl Res
2023Functional
Analysis of performance, bone characteristics, and expression of genes involved in the balance of ionic concentrations in broilers subjected to dietary electrolyte balance levels.
Araujo AC et al.·Br Poult Sci
2022
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