SLC8A2

Chr 19

solute carrier family 8 member A2

Also known as: NCX2

NCBI Gene: 6543 ENSG00000118160 UniProt: Q9UPR5 OMIM: 601901

The protein mediates electrogenic exchange of calcium and sodium ions across cell membranes, contributing to cytoplasmic calcium homeostasis in excitable cells and modulating synaptic plasticity, learning and memory. Mutations cause neurodevelopmental disorders with intellectual disability and seizures. This gene follows autosomal recessive inheritance and is highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable calcium:monoatomic cation antiporter activity involved in regulation of postsynaptic cytosolic calcium ion concentration and calcium:sodium antiporter activity. Predicted to be involved in several processes, including learning or memory; monoatomic cation transmembrane transport; and regulation of short-term neuronal synaptic plasticity. Predicted to act upstream of or within several processes, including modulation of chemical synaptic transmission; regulation of action potential firing pattern; and response to ischemia. Located in presynapse. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.26

Clinical Summary— SLC8A2

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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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ClinVar Variants

80 VUS of 98 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.26LOEUF

pLI 0.996

Z-score 4.55

OE 0.10 (0.04–0.26)

Highly constrained

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

Missense Constraint?

5.24Z-score

OE missense 0.39 (0.35–0.43)

224 obs / 578.6 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.26)

0≤0.351.4

Missense OE?0.39 (0.35–0.43)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 3 / 29.8Missense obs/exp: 224 / 578.6Syn Z: 1.51

This gene — mechanism propensity

0.5772th %ile

GOF

0.72top 25%

LOF

0.52top 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 0.26

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.

ClinVar Variant Classifications

98 submitted variants in ClinVar

ClinVar

Classification Summary

VUS80

Likely Benign9

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	80	0	0	80
Likely Benign	1	0	8	9
Benign	0	1	1	2
Total	81	1	9	91

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap SLC8A2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →