SLC38A8

Chr 16AR

solute carrier family 38 member 8

ENSG00000166558 UniProt: A6NNN8 OMIM: 615585

This gene encodes a sodium-dependent amino acid transporter that facilitates uptake of glutamine, alanine, histidine, aspartate, and arginine in neurons. Autosomal recessive mutations cause foveal hypoplasia with or without optic nerve misrouting and anterior segment dysgenesis, affecting ocular development and vision. The gene shows very low constraint against loss-of-function variants (pLI near zero), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Electrogenic sodium-dependent amino acid transporter with a preference for L-glutamine, L-alanine, L-histidine, L-aspartate and L-arginine. May facilitate glutamine uptake in both excitatory and inhibitory neurons. The transport mechanism and stoichiometry remain to be elucidated

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.901 OMIM phenotype

Clinical Summary— SLC38A8

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Gene-Disease Validity (ClinGen)

foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.90LOEUF

pLI 0.000

Z-score -2.06

OE 1.50 (1.11–1.90)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-4.34Z-score

OE missense 1.74 (1.61–1.88)

472 obs / 270.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.50 (1.11–1.90)

0≤0.351.4

Missense OE?1.74 (1.61–1.88)

0≤0.61.4

Synonymous OE?1.84

0≤1.21.6

LoF obs/exp: 30 / 20.1Missense obs/exp: 472 / 270.9Syn Z: -7.31

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC38A8-related foveal hypoplasia with or without optic nerve misrouting and/or anterior segment dysgenesisLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6745th %ile

GOF

0.80top 10%

LOF

0.2582th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.