SLC9A6

Chr XX-linkedXLD

solute carrier family 9 member A6

ENSG00000198689 UniProt: Q92581 OMIM: 300231

The protein is a sodium-hydrogen exchanger that localizes to early and recycling endosomes where it regulates endosomal pH and volume. Mutations cause X-linked syndromic intellectual developmental disorder (Christianson type) in males and X-linked neurodegenerative disorder with parkinsonism and cognitive impairment in females. Loss-of-function mutations disrupt endosomal function, leading to these distinct X-linked phenotypes that differ by sex.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Endosomal Na(+), K(+)/H(+) antiporter (PubMed:15522866, PubMed:28635961, PubMed:31676550, PubMed:32277048). Mediates the electroneutral exchange of endosomal luminal H(+) for a cytosolic Na(+) or K(+). By facilitating proton efflux, SLC9A6 counteracts the acidity generated by vacuolar (V)-ATPase, thereby limiting luminal acidification. Responsible for alkalizing and maintaining the endosomal pH, and consequently in, e.g., endosome maturation and trafficking of recycling endosomal cargo (PubMed:15522866, PubMed:28635961, PubMed:31676550, PubMed:32277048). Plays a critical role during neurodevelopment by regulating synaptic development and plasticity (By similarity). Implicated in the maintenance of cell polarity in a manner that is dependent on its ability to modulate intravesicular pH (PubMed:20130086). Regulates intracellular pH in some specialized cells, osteoclasts and stereocilia where this transporter localizes to the plasma membrane (By similarity)

OMIM ResearchGenerating clinical summary…

LOFmechanismX-linked/XLDLOEUF 0.212 OMIM phenotypes

VCEP Guidelines: Rett/Angelman-like DisordersPilot

View Specifications ClinGen Panel

Clinical Summary— SLC9A6

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Gene-Disease Validity (ClinGen)

Christianson syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 0.998

Z-score 4.26

OE 0.04 (0.01–0.21)

Highly constrained

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

Missense Constraint?

2.95Z-score

OE missense 0.50 (0.43–0.57)

137 obs / 274.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.21)

0≤0.351.4

Missense OE?0.50 (0.43–0.57)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 1 / 23.1Missense obs/exp: 137 / 274.8Syn Z: 0.36

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC9A6-related syndromic intellectual developmental disorder, Christianson typeLOFXLR

This gene — mechanism propensity

0.5082th %ile

GOF

0.6736th %ile

LOF

0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). 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.

LOFLOEUF 0.21 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOFprediction 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.