SLC9A8
Chr 20solute carrier family 9 member A8
Also known as: NHE-8, NHE8
SLC9A8 encodes a sodium-hydrogen antiporter that exchanges intracellular H+ for extracellular Na+ in 1:1 stoichiometry, functioning primarily in the trans-Golgi to regulate pH and protein trafficking, and also contributing to intestinal sodium absorption and retinal pigment epithelium pH homeostasis. Mutations cause autosomal recessive intellectual developmental disorder with seizures, microcephaly, and cerebellar atrophy. This gene is not constrained against loss-of-function variants, consistent with its recessive inheritance pattern.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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.
ClinVar Variant Classifications
102 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 7 | 0 | 7 |
Likely Pathogenic | 0 | 0 | 2 | 0 | 2 |
VUS | 0 | 57 | 3 | 0 | 60 |
Likely Benign | 0 | 2 | 0 | 3 | 5 |
Benign | 0 | 0 | 0 | 0 | 0 |
| Total | 0 | 59 | 12 | 3 | 74 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
SLC9A8 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools