SLC9A8

Chr 20

solute carrier family 9 member A8

Also known as: NHE-8, NHE8

NCBI Gene: 23315 ENSG00000197818 UniProt: Q9Y2E8 OMIM: 612730

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.

OMIM ResearchSummary from RefSeq, UniProt

Sodium-hydrogen exchangers (NHEs), such as SLC9A8, are integral transmembrane proteins that exchange extracellular Na+ for intracellular H+. NHEs have multiple functions, including intracellular pH homeostasis, cell volume regulation, and electroneutral NaCl absorption in epithelia (Xu et al., 2008 [PubMed 18209477]).[supplied by OMIM, Apr 2009]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.01

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.01LOEUF

pLI 0.000

Z-score 1.50

OE 0.69 (0.48–1.01)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.62Z-score

OE missense 0.76 (0.68–0.84)

266 obs / 351.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.69 (0.48–1.01)

0≤0.351.4

Missense OE?0.76 (0.68–0.84)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 19 / 27.5Missense obs/exp: 266 / 351.4Syn Z: -0.63

Background carrier burden — how many people carry a rare variant somewhere in SLC9A8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 90

653 rare PASS variants

Rare truncating (LoF)

1 in 1,000

141 rare PASS variants

Rare synonymous (reference)

1 in 100

297 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SLC9A8. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 430
South Asian	~43k	1 in 120	1 in 500
Remaining (unassigned)	~30k	1 in 79	1 in 1,600
European (Finnish)	~27k	1 in 250	1 in 1,200
Admixed American	~22k	1 in 90	1 in 610
African / African American	~21k	1 in 130	1 in 1,200
East Asian	~20k	1 in 140	1 in 300
Ashkenazi Jewish	~13k	1 in 350	1 in 2,000
Middle Eastern	~2,884	1 in 120	≈ 1 in 720

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 16 coding exons well covered in gnomAD exomes; exons 1, 4 marginal. Genomes: all 16.? see exons ↓