SLC9A1

protein-coding

solute carrier family 9 member A1, the group of Protein phosphatase 1 regulatory subunits|Solute carrier family 9

Gene summary

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]

Previous symbols:

APNH
NHE1
NHE-1

MANE transcript

NM_003047.5

Inheritance

ClinVar variants

P:6U:142B:91

Top phenotype

Spinocerebellar ataxia, autosomal recessive 19 (Lichtenstein-Knorr syndrome)

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr1:27,098,809-27,166,981

External References & Databases

Ensembl (ENSG00000090020)

Transcript & Mutation Effects

hg38 • Region Span ~68.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Lichtenstein-Knorr syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014572

Submitter: PanelApp Australia

Lichtenstein-Knorr syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014572

Submitter: Labcorp Genetics (formerly Invitae)

Lichtenstein-Knorr syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014572

Submitter: ClinGen

*SLC9A1* was first reported in relation to autosomal recessive Lichtenstein-Knorr syndrome in 2015 (Guissart et al, PMID: 25205112). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Four variants (missense, nonsense, frameshift) that have been reported in four probands in four publications (PMIDs: 25205112, 30018422, 30237576, 36561016) are included in this curation. Patients with recessive *SLC9A1* variants have mainly been reported to exhibit early-onset cerebellar ataxia, seizures, cerebral atrophy and variable hearing loss (PMID: 25205112, 30018422, 36561016). Recently Pellerin, Ceravolo, and colleagues reported individuals from consanguineous families carrying recessive *SLC9A1* variants presenting with amelogenesis imperfecta in addition to early-onset cerebellar ataxia associated with cerebellar atrophy, developmental delay, and variable sensorineural hearing loss (Journal of the Neurological Sciences, Volume 455, 121930). This gene-disease relationship is supported by animal model and expression studies. *SLC9A1* is shown to be ubiquitously expressed in various tissues throughout the body (PMID: 23715323, dbGaP Accession phs000424.v10.p2). Homozygous SLC9A1 null mutant mice models showed reduced postnatal growth, ataxia, and epileptic-like seizures without cerebellar atrophy (PMID: 10199808). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date July 9th, 2025 (SOP Version 11).

Lichtenstein-Knorr syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014572

Submitter: Orphanet

Lichtenstein-Knorr syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014572

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive 19 (Lichtenstein-Knorr syndrome)AR

Manifestation: Audiologic/Otolaryngologic; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25205112

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC9A1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 201

not specifiedTotal: 82

SLC9A1-related disorderTotal: 33

Lichtenstein-Knorr syndromeTotal: 9

Inborn genetic diseasesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003047.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	86 clinvar	2 clinvar	93
missense		2 clinvar	129 clinvar	2 clinvar	1 clinvar	134
nonsense	1 clinvar					1
start loss						0
frameshift	2 clinvar	1 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	3	3	142	88	3	239

Highest pathogenic variant AF is 0.0000020524637

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003047.5	RefSeq	NP_003038.2	12	MANE Select
ENST00000263980.8	Ensembl	ENSP00000263980.3	12	MANE Select
ENST00000374084.2	Ensembl	ENSP00000363197.2	2	Standard
ENST00000374086.3	Ensembl	ENSP00000363199.3	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac muscle contraction - Homo sapiens (human)
Bile secretion - Homo sapiens (human)
Gastric acid secretion - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)
Thyroid hormone signaling pathway - Homo sapiens (human)

Biological Process

ion transport
cellular sodium ion homeostasis
regulation of pH
response to acidic pH
positive regulation of cardiac muscle hypertrophy

Molecular Function

protein binding
calmodulin binding
phosphatidylinositol-4,5-bisphosphate binding
solute:proton antiporter activity
sodium:proton antiporter activity

Cellular Component

nucleoplasm
cytoplasm
mitochondrion
endoplasmic reticulum
endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263980
Coding exons: 12
Length: 68167
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125748
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.55	292	520	0.562	0.0000342	5301
Missense (PolyPhen)		63	188.83	0.33363		2028
Synonymous	1.66	204	237	0.862	0.0000175	1724
Loss of Function	4.22	6	31.6	0.190	0.00000179	334

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000058	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction. {ECO:0000269|PubMed:11350981, ECO:0000269|PubMed:15035633, ECO:0000269|PubMed:8901634}.;
Disease: DISEASE: Lichtenstein-Knorr syndrome (LIKNS) [MIM:616291]: An autosomal recessive neurologic disorder characterized by progressive cerebellar ataxia and severe progressive sensorineural hearing loss. {ECO:0000269|PubMed:25205112}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.460

Intolerance Scores

LoFtool: 0.387
RVIS EVS: -1.62
RVIS percentile EVS: 2.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.904

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium