SLC9A3

Chr 5AR

solute carrier family 9 member A3

ENSG00000066230 UniProt: P48764 OMIM: 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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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)

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.311 OMIM phenotype

Clinical Summary— SLC9A3

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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.

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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 153 VUS of 365 total submissions

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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 OE?0.16 (0.09–0.31)

0≤0.351.4

Missense OE?0.69 (0.64–0.76)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 6 / 38.2Missense obs/exp: 365 / 525.7Syn Z: -2.05

This gene — mechanism propensity

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.

LOF65% 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

365 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic4

VUS153

Likely Benign136

Benign32

Conflicting8

Pathogenic

Likely Pathogenic

153

VUS

136

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	4	1	0	13
Likely Pathogenic	3	1	0	0	4
VUS	2	146	5	0	153
Likely Benign	0	8	51	77	136
Benign	0	3	15	14	32
Conflicting	—				8
Total	13	162	72	91	346

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

View in ClinVar →

111 pathogenic / likely-pathogenic (of 142) ClinVar copy-number / structural variants overlap SLC9A3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →