SLC9A6

Chr XX-linkedXLD

solute carrier family 9 member A6

Also known as: MRSA, MRXSCH, NDPACX, NHE6

NCBI Gene: 10479ENSG00000198689UniProt: Q92581

This gene encodes a sodium-hydrogen exchanger that is amember of the solute carrier family 9. The encoded protein localizes to early and recycling endosomes and may be involved in regulating endosomal pH and volume. Defects in this gene are associated with X-linked syndromic cognitive disability, Christianson type. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, Christianson typeMIM #300243
X-linked
Neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairmentMIM #301142
XLD
959
ClinVar variants
46
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— SLC9A6
⚡
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.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 151 VUS of 959 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.21LOEUF
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?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.
2.95Z-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?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.0.04 (0.01–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.50 (0.43–0.57)
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.0.96
0≤1.21.6
LoF obs/exp: 1 / 23.1Missense obs/exp: 137 / 274.8Syn Z: 0.36

ClinVar Variant Classifications

959 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic17
VUS151
Likely Benign128
Benign24
Conflicting2
29
Pathogenic
17
Likely Pathogenic
151
VUS
128
Likely Benign
24
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
23
0
29
Likely Pathogenic
10
6
1
0
17
VUS
3
130
15
3
151
Likely Benign
0
6
57
65
128
Benign
0
3
17
4
24
Conflicting
—2
Total1914511372351

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC9A6 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SLC9A6-related syndromic intellectual developmental disorder, Christianson type

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, X-linked syndromic, Christianson type

MIM #300243

Molecular basis of disorder known

X-linked

Neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment

MIM #301142

Molecular basis of disorder known

X-linked dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
X-Linked Epilepsies: A Narrative Review.
Bernardo P et al.·Int J Mol Sci
2024Review
Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods.
McKnight D et al.·Hum Mutat
2022
SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population.
Mir A et al.·Hum Genet
2022
Structural and functional implications of SLC13A3 and SLC9A6 mutations: an in silico approach to understanding intellectual disability.
Hussain SI et al.·BMC Neurol
2023Functional
Functional analysis of two SLC9A6 frameshift variants in lymphoblastoid cells from patients with Christianson syndrome.
He H et al.·CNS Neurosci Ther
2023Cohort
The expanding phenotypic spectrum of female SLC9A6 mutation carriers: a case series and review of the literature.
Sinajon P et al.·Hum Genet
2016Review
Genetic disorders associated with postnatal microcephaly.
Seltzer LE et al.·Am J Med Genet C Semin Med Genet
2014Review
Missense variants in SLC9A6 cause partial epilepsy without neurodevelopmental delay.
Jiao JP et al.·Orphanet J Rare Dis
2025
Christianson syndrome: A novel splicing variant of SLC9A6 causes exon skipping in a Chinese boy and a literature review.
Zhang X et al.·J Clin Lab Anal
2022Case report
Donor Splice Site Variant in SLC9A6 Causes Christianson Syndrome in a Lithuanian Family: A Case Report.
Petraitytė G et al.·Medicina (Kaunas)
2022Case report
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
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools