SLC38A8

Chr 16AR

solute carrier family 38 member 8

Also known as: FHASD, FVH2, SNAT8

NCBI Gene: 146167 ENSG00000166558 UniProt: A6NNN8

This gene encodes a putative sodium-dependent amino-acid/proton antiporter. The protein has eleven transmembrane domains, an extracellular N-terminus and an intracellular C-terminal tail. The protein is a member of the SLC38 sodium-coupled neutral amino acid transporter family of proteins. Mutations in this gene result in foveal hypoplasia with or without optic nerve misrouting and/or anterior segment dysgenesis. [provided by RefSeq, May 2014]

Primary Disease Associations & Inheritance

Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesisMIM #609218

Active trials

Pathogenic / LP

500

ClinVar variants

Pubs (1 yr)

-4.3

Missense Z

1.90

LOEUF

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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ClinVar Variants

61 Pathogenic / Likely Pathogenic· 37 VUS of 500 total submissions

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GeneReview available — SLC38A8

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-4.34Z-score

OE missense 1.74 (1.61–1.88)

472 obs / 270.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.50 (1.11–1.90)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.74 (1.61–1.88)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.84

0≤1.21.6

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

0.6745th %ile

GOF

0.80top 10%

LOF

0.2582th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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.