SLC38A8

Summary

SLC38A8 (solute carrier family 38 member 8, HGNC:32434) is a protein-coding gene on chromosome 16q23.3, encoding Solute carrier family 38 member 8 (A6NNN8). Electrogenic sodium-dependent amino acid transporter with a preference for L-glutamine, L-alanine, L-histidine, L-aspartate and L-arginine.

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.

Source: NCBI Gene 146167 — RefSeq curated summary.

At a glance

• Gene–disease (curated): foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 765 total — 49 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 13
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001080442

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32434
Approved symbol	SLC38A8
Name	solute carrier family 38 member 8
Location	16q23.3
Locus type	gene with protein product
Status	Approved
Aliases	SNAT8
Ensembl gene	ENSG00000166558
Ensembl biotype	protein_coding
OMIM	615585
Entrez	146167

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 retained_intron

ENST00000299709, ENST00000568003, ENST00000568178, ENST00000569816, ENST00000912183, ENST00000946738

RefSeq mRNA: 1 — MANE Select: NM_001080442 NM_001080442

CCDS: CCDS32495

Canonical transcript exons

ENST00000299709 — 11 exons

Exon	Start	End
ENSE00001104170	84033328	84033469
ENSE00001104176	84022775	84022889
ENSE00001104177	84029494	84029551
ENSE00001104184	84031867	84031968
ENSE00001276275	84016519	84016727
ENSE00001276279	84017140	84017287
ENSE00001290427	84009667	84009877
ENSE00002605281	84041969	84042159
ENSE00003471004	84036702	84036900
ENSE00003674267	84013001	84013052
ENSE00003899390	84042551	84042795

Expression profiles

Bgee: expression breadth broad, 80 present calls, max score 82.27.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1004 / max 118.6581, expressed in 21 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158323	0.0629	12
158324	0.0324	7
158322	0.0052	1

Top tissues by expression

111 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.27	silver quality
amygdala	UBERON:0001876	70.06	gold quality
temporal lobe	UBERON:0001871	70.01	gold quality
prefrontal cortex	UBERON:0000451	68.69	gold quality
frontal cortex	UBERON:0001870	66.08	gold quality
Brodmann (1909) area 9	UBERON:0013540	63.85	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	63.30	gold quality
hypothalamus	UBERON:0001898	63.24	gold quality
superior frontal gyrus	UBERON:0002661	62.50	gold quality
right frontal lobe	UBERON:0002810	62.37	gold quality
cerebral cortex	UBERON:0000956	61.88	gold quality
anterior cingulate cortex	UBERON:0009835	60.99	gold quality
pituitary gland	UBERON:0000007	58.27	gold quality
primary visual cortex	UBERON:0002436	57.70	gold quality
islet of Langerhans	UBERON:0000006	56.13	gold quality
adenohypophysis	UBERON:0002196	55.85	gold quality
brain	UBERON:0000955	55.78	gold quality
Ammon’s horn	UBERON:0001954	52.13	gold quality
heart left ventricle	UBERON:0002084	52.12	gold quality
putamen	UBERON:0001874	51.74	gold quality
caudate nucleus	UBERON:0001873	48.86	gold quality
nucleus accumbens	UBERON:0001882	48.69	gold quality
substantia nigra	UBERON:0002038	47.94	gold quality
hindlimb stylopod muscle	UBERON:0004252	47.60	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	47.22	gold quality
duodenum	UBERON:0002114	46.05	gold quality
adrenal tissue	UBERON:0018303	45.70	silver quality
right adrenal gland cortex	UBERON:0035827	44.66	gold quality
heart	UBERON:0000948	44.15	gold quality
right hemisphere of cerebellum	UBERON:0014890	43.86	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting SLC38A8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-338-3P	98.14	67.38	1137
HSA-MIR-3928-3P	97.61	66.53	1096

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 8)

• Isolated foveal hypoplasia with secondary nystagmus and low vision is associated with a homozygous SLC38A8 mutation. (PMID:24045842)
• Study found that SNP rs9931086 in the SLC38A8 gene and genes CTLA-4, HDAC, and PPAR-alpha, which are involved in inflammatory processes, may modify the effects of occupational exposure on lung function. (PMID:24289273)
• Recessive mutations in SLC38A8 cause foveal hypoplasia and optic nerve misrouting without albinism. (PMID:24290379)
• The pathogenicity of SLC38A8 in five families with foveal hypoplasia and congenital nystagmus. (PMID:32032626)
• SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization. (PMID:32744312)
• Novel Biallelic Variants and Phenotypic Features in Patients with SLC38A8-Related Foveal Hypoplasia. (PMID:33498813)
• Genetic causes of nystagmus, foveal hypoplasia and subnormal visual acuity- other than albinism. (PMID:33594928)
• The Phenotypic and Mutational Spectrum of the FHONDA Syndrome and Oculocutaneous Albinism: Similarities and Differences. (PMID:35029636)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc38a8a	ENSDARG00000009482
danio_rerio	slc38a8b	ENSDARG00000054196
mus_musculus	Slc38a8	ENSMUSG00000034224
rattus_norvegicus	Slc38a8	ENSRNOG00000025503
drosophila_melanogaster	CG16700	FBGN0030816
drosophila_melanogaster	CG4991	FBGN0030817
drosophila_melanogaster	CG13384	FBGN0032036
drosophila_melanogaster	polyph	FBGN0033572
drosophila_melanogaster	VGAT	FBGN0033911
drosophila_melanogaster	acs	FBGN0035300
drosophila_melanogaster	CG7888	FBGN0036116
drosophila_melanogaster	CG32079	FBGN0052079
drosophila_melanogaster	CG32081	FBGN0052081
drosophila_melanogaster	mah	FBGN0285912
caenorhabditis_elegans		WBGENE00006783
caenorhabditis_elegans	slc-36.4	WBGENE00010421
caenorhabditis_elegans	Y18D10A.23	WBGENE00012487
caenorhabditis_elegans		WBGENE00012629
caenorhabditis_elegans		WBGENE00012804
caenorhabditis_elegans		WBGENE00019837
caenorhabditis_elegans		WBGENE00020837

Paralogs (15): SLC38A5 (ENSG00000017483), SLC32A1 (ENSG00000101438), SLC38A7 (ENSG00000103042), SLC38A1 (ENSG00000111371), SLC36A1 (ENSG00000123643), SLC38A2 (ENSG00000134294), SLC38A4 (ENSG00000139209), SLC38A6 (ENSG00000139974), SLC38A10 (ENSG00000157637), SLC38A11 (ENSG00000169507), SLC38A9 (ENSG00000177058), SLC36A4 (ENSG00000180773), SLC36A3 (ENSG00000186334), SLC36A2 (ENSG00000186335), SLC38A3 (ENSG00000188338)

Protein

Protein identifiers

Solute carrier family 38 member 8 — A6NNN8 (reviewed: A6NNN8)

Alternative names: Amino acid transporter SLC38A8

All UniProt accessions (3): A6NNN8, H3BP02, H3BUP5

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subcellular location. Membrane. Cytoplasm. Cell cortex. Cell projection. Axon.

Tissue specificity. Expressed in fetal and adult brain, and spinal cord. In the brain, it is localized in the cell body and axon of the majority of neuronal cells and in a subset of glial cells. Found throughout the neuronal retina, with higher expression levels in the inner and outer plexiform layers and the photoreceptor layer. Very weak expression is also present in the kidneys, thymus, and testes.

Disease relevance. Foveal hypoplasia 2 (FVH2) [MIM:609218] An isolated form of foveal hypoplasia, a developmental defect of the eye defined as the lack of foveal depression with continuity of all neurosensory retinal layers in the presumed foveal area. Clinical features include absence of foveal pit on optical coherence tomography, absence of foveal hyperpigmentation, absence of foveal avascularity, absence of foveal and macular reflexes, decreased visual acuity, and nystagmus. Optic nerve misrouting and anterior segment dysgenesis are observed in some FVH2 patients. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the amino acid/polyamine transporter 2 family.

RefSeq proteins (1): NP_001073911* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013057	AA_transpt_TM	Domain

Pfam: PF01490

Catalyzed reactions (Rhea), 6 shown:

• L-arginine(in) = L-arginine(out) (RHEA:32143)
• L-aspartate(out) = L-aspartate(in) (RHEA:66332)
• L-alanine(in) = L-alanine(out) (RHEA:70719)
• L-histidine(out) = L-histidine(in) (RHEA:72807)
• L-leucine(in) = L-leucine(out) (RHEA:73011)
• L-glutamine(out) = L-glutamine(in) (RHEA:73419)

UniProt features (19 total): transmembrane region 11, sequence variant 7, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NNN8-F1	83.83	0.54

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 86 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GOBP_CRANIAL_NERVE_DEVELOPMENT, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_OPTIC_NERVE_DEVELOPMENT, GOBP_AMINO_ACID_TRANSPORT, GOBP_NERVE_DEVELOPMENT, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_VIRAL_GENOME_REPLICATION, GOBP_VIRAL_LIFE_CYCLE, GOBP_ORGANIC_ACID_METABOLIC_PROCESS

GO Biological Process (11): amino acid transmembrane transport (GO:0003333), retinal pigment epithelium development (GO:0003406), aspartate metabolic process (GO:0006531), visual perception (GO:0007601), response to virus (GO:0009615), viral genome replication (GO:0019079), optic nerve development (GO:0021554), neuron projection development (GO:0031175), amino acid transport (GO:0006865), retina development in camera-type eye (GO:0060041), L-alpha-amino acid transmembrane transport (GO:1902475)

GO Molecular Function (1): L-amino acid transmembrane transporter activity (GO:0015179)

GO Cellular Component (5): cell cortex (GO:0005938), membrane (GO:0016020), axon (GO:0030424), cytoplasm (GO:0005737), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
amino acid transport	1
transmembrane transport	1
retina development in camera-type eye	1
epithelium development	1
amino acid metabolic process	1
dicarboxylic acid metabolic process	1
sensory perception of light stimulus	1
response to other organism	1
viral process	1
viral life cycle	1
cranial nerve development	1
neuron development	1
plasma membrane bounded cell projection organization	1
transport	1
camera-type eye development	1
anatomical structure development	1
amino acid transmembrane transport	1
L-amino acid transport	1
carboxylic acid transmembrane transport	1
amino acid transmembrane transporter activity	1
carboxylic acid transmembrane transporter activity	1
L-alpha-amino acid transmembrane transport	1
cytoplasm	1
cell periphery	1
neuron projection	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

552 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC38A8	GPR143	P51810	658
SLC38A8	FRMD7	Q6ZUT3	645
SLC38A8	SLC38A9	Q8NBW4	575
SLC38A8	NECAB2	Q7Z6G3	536
SLC38A8	HPS6	Q86YV9	506
SLC38A8	SLC25A35	Q3KQZ1	456
SLC38A8	LRMDA	Q9H2I8	451
SLC38A8	PLPPR4	Q7Z2D5	446
SLC38A8	HPS3	Q969F9	435
SLC38A8	OCA2	Q04671	431
SLC38A8	HPS5	Q9UPZ3	430
SLC38A8	SVOPL	Q8N434	430
SLC38A8	SLC3A1	Q07837	414
SLC38A8	SLC7A3	Q8WY07	399
SLC38A8	SLC7A8	Q9UHI5	393

IntAct

3 interactions, top by confidence:

A	B	Type	Score
SLC38A8	G3BP2	psi-mi:“MI:0407”(direct interaction)	0.440
SLC38A8	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (26): ATP2B4 (Affinity Capture-MS), C14orf2 (Affinity Capture-MS), ATP5F1 (Affinity Capture-MS), CDS1 (Affinity Capture-MS), CHPT1 (Affinity Capture-MS), CMTM4 (Affinity Capture-MS), DDX50 (Affinity Capture-MS), ENPP1 (Affinity Capture-MS), FAAH (Affinity Capture-MS), FIS1 (Affinity Capture-MS), GBA2 (Affinity Capture-MS), GOLGA5 (Affinity Capture-MS), GPR180 (Affinity Capture-MS), ILVBL (Affinity Capture-MS), IRGQ (Affinity Capture-MS)

ESM2 similar proteins: A1YG32, A2VCW5, A2VE31, A6NNN8, A7E3U5, A8KBL5, D3Z813, F4KBM7, G3UVW3, O80668, P40074, Q08AI6, Q0WQJ3, Q28HE5, Q28I47, Q3U1J0, Q3USY0, Q503G8, Q5E9S9, Q5EA97, Q5F468, Q5HZH7, Q5R443, Q5R9F5, Q5RE87, Q5SPB1, Q5XH90, Q6DEL1, Q6DFE7, Q6JWR2, Q6WWW3, Q8BWH0, Q8CFE6, Q8HXI3, Q8IZM9, Q8K2P7, Q8R1S9, Q8WUX1, Q969I6, Q96QD8

Diamond homologs: A6NNN8, A7E3U5, Q28I47, Q5HZH7, Q5R9F5, Q5RE87, Q6DEL1, Q6DFE7, Q6JWR2, Q8BWH0, Q969I6, Q9NVC3, A1YG32, A2VCW5, A2VE31, G3UVW3, Q28HE5, Q3U1J0, Q503G8, Q5E9S9, Q5F468, Q5R443, Q5SPB1, Q5XH90, Q6WWW3, Q8CFE6, Q8IZM9, Q8K2P7, Q8R1S9, Q8WUX1, Q96QD8, Q99624, Q9DCP2, Q9EQ25, Q9H2H9, Q9JHE5, Q9JHZ9, Q9JM15, Q9LXF8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

765 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	49
Likely pathogenic	27
Uncertain significance	154
Likely benign	455
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
125442	NM_001080442.3(SLC38A8):c.95T>G (p.Ile32Ser)	Pathogenic
125443	NM_001080442.3(SLC38A8):c.707T>A (p.Val236Asp)	Pathogenic
125444	NM_001080442.3(SLC38A8):c.1002del (p.Ser336fs)	Pathogenic
125445	NM_001080442.3(SLC38A8):c.1234G>A (p.Gly412Arg)	Pathogenic
125448	NM_001080442.3(SLC38A8):c.842CTG[1] (p.Ala282del)	Pathogenic
1301567	NM_001080442.3(SLC38A8):c.116del (p.Gly39fs)	Pathogenic
2423639	NC_000016.9:g.(?84050104)(84050912_?)del	Pathogenic
2700790	NM_001080442.3(SLC38A8):c.495dup (p.Ala166fs)	Pathogenic
2708550	NM_001080442.3(SLC38A8):c.385A>T (p.Lys129Ter)	Pathogenic
2712517	NM_001080442.3(SLC38A8):c.951dup (p.Arg318fs)	Pathogenic
2738843	NM_001080442.3(SLC38A8):c.797C>G (p.Ser266Ter)	Pathogenic
2740171	NM_001080442.3(SLC38A8):c.558C>G (p.Tyr186Ter)	Pathogenic
2776024	NM_001080442.3(SLC38A8):c.323dup (p.Leu109fs)	Pathogenic
2779315	NM_001080442.3(SLC38A8):c.585C>G (p.Tyr195Ter)	Pathogenic
2785810	NM_001080442.3(SLC38A8):c.688C>T (p.Gln230Ter)	Pathogenic
2791239	NM_001080442.3(SLC38A8):c.272_273dup (p.Val92fs)	Pathogenic
2795197	NM_001080442.3(SLC38A8):c.562del (p.Ala188fs)	Pathogenic
2798185	NM_001080442.3(SLC38A8):c.421_424dup (p.Pro142fs)	Pathogenic
2837016	NM_001080442.3(SLC38A8):c.359dup (p.Arg121fs)	Pathogenic
2859559	NM_001080442.3(SLC38A8):c.434G>A (p.Trp145Ter)	Pathogenic
2863639	NM_001080442.3(SLC38A8):c.141G>A (p.Trp47Ter)	Pathogenic
2901978	NM_001080442.3(SLC38A8):c.964C>T (p.Gln322Ter)	Pathogenic
2905217	NM_001080442.3(SLC38A8):c.263del (p.Tyr88fs)	Pathogenic
2964446	NM_001080442.3(SLC38A8):c.11del (p.Gln4fs)	Pathogenic
2972771	NM_001080442.3(SLC38A8):c.376del (p.Gln126fs)	Pathogenic
2985445	NM_001080442.3(SLC38A8):c.160G>T (p.Gly54Ter)	Pathogenic
2985546	NM_001080442.3(SLC38A8):c.724del (p.Met242fs)	Pathogenic
2994943	NM_001080442.3(SLC38A8):c.995dup (p.Trp333fs)	Pathogenic
3021960	NM_001080442.3(SLC38A8):c.403dup (p.Leu135fs)	Pathogenic
3243590	NC_000016.9:g.(?84075554)(84075762_?)del	Pathogenic

SpliceAI

1926 predictions. Top by Δscore:

Variant	Effect	Δscore
16:84012999:A:AC	donor_gain	1.0000
16:84013000:C:CC	donor_gain	1.0000
16:84016513:CCTCA:C	donor_loss	1.0000
16:84016514:CTCA:C	donor_loss	1.0000
16:84016515:TCA:T	donor_loss	1.0000
16:84016516:CA:C	donor_loss	1.0000
16:84016517:A:AG	donor_loss	1.0000
16:84016518:C:CT	donor_loss	1.0000
16:84029552:C:CC	acceptor_gain	1.0000
16:84033322:CCTTA:C	donor_loss	1.0000
16:84033323:CTTAC:C	donor_loss	1.0000
16:84033324:TTAC:T	donor_loss	1.0000
16:84033325:TACCT:T	donor_loss	1.0000
16:84033327:C:A	donor_loss	1.0000
16:84033466:CACA:C	acceptor_gain	1.0000
16:84033468:CA:C	acceptor_gain	1.0000
16:84033470:C:CC	acceptor_gain	1.0000
16:84036696:ACTT:A	donor_loss	1.0000
16:84036697:CTT:C	donor_loss	1.0000
16:84036698:TTAC:T	donor_loss	1.0000
16:84036699:TA:T	donor_loss	1.0000
16:84036700:A:AC	donor_gain	1.0000
16:84036700:ACG:A	donor_gain	1.0000
16:84036700:ACGCT:A	donor_loss	1.0000
16:84036701:C:CA	donor_gain	1.0000
16:84036701:CG:C	donor_gain	1.0000
16:84036701:CGC:C	donor_gain	1.0000
16:84036701:CGCT:C	donor_gain	1.0000
16:84036701:CGCTT:C	donor_gain	1.0000
16:84041966:T:TG	donor_loss	1.0000

AlphaMissense

2783 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:84016544:A:C	S379R	0.994
16:84016544:A:T	S379R	0.994
16:84016546:T:G	S379R	0.994
16:84017265:A:C	F276L	0.990
16:84017265:A:T	F276L	0.990
16:84017267:A:G	F276L	0.990
16:84017287:C:T	G269E	0.987
16:84029501:C:T	G228E	0.987
16:84016621:A:G	W354R	0.986
16:84016621:A:T	W354R	0.986
16:84017278:C:T	G272D	0.986
16:84022775:C:A	G269W	0.986
16:84029497:A:C	F229L	0.986
16:84029497:A:T	F229L	0.986
16:84029499:A:G	F229L	0.986
16:84009836:C:T	G419D	0.984
16:84009837:C:G	G419R	0.984
16:84029508:A:G	C226R	0.984
16:84036877:G:C	S71R	0.984
16:84036877:G:T	S71R	0.984
16:84036879:T:G	S71R	0.984
16:84029502:C:A	G228W	0.983
16:84022775:C:G	G269R	0.982
16:84022775:C:T	G269R	0.982
16:84029498:A:G	F229S	0.982
16:84013047:A:G	C390R	0.981
16:84017239:A:G	L285S	0.981
16:84042011:G:C	F49L	0.981
16:84042011:G:T	F49L	0.981
16:84042013:A:G	F49L	0.981

dbSNP variants (sampled 300 via entrez): RS1000121079 (16:84011728 A>C), RS1000145029 (16:84034286 A>C), RS1000211178 (16:84039458 AG>A,AGG), RS1000251274 (16:84023518 A>C), RS1000257622 (16:84030862 C>T), RS1000266742 (16:84014377 C>T), RS1000328942 (16:84010037 C>G,T), RS1000423261 (16:84021086 G>C), RS1000439772 (16:84036950 C>A,T), RS1000476564 (16:84025581 C>G,T), RS1000496730 (16:84040947 C>G,T), RS1000540011 (16:84012416 C>A,T), RS1000563798 (16:84027266 C>A), RS1000596011 (16:84023738 A>G), RS1000689357 (16:84032403 G>A,T)

Disease associations

OMIM: gene MIM:615585 | disease phenotypes: MIM:609218, MIM:136520, MIM:204000

GenCC curated gene-disease

Disease	Classification	Inheritance
foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome	Definitive	AR

Mondo (4): foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome (MONDO:0012216), foveal hypoplasia (MONDO:0044203), Leber congenital amaurosis (MONDO:0018998), isolated foveal hypoplasia (MONDO:0034978)

Orphanet (3): Foveal hypoplasia-optic nerve decussation defect-anterior segment dysgenesis syndrome (Orphanet:397618), Leber congenital amaurosis (Orphanet:65), Isolated foveal hypoplasia (Orphanet:519398)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000568	Microphthalmia
HP:0000627	Posterior embryotoxon
HP:0000639	Nystagmus
HP:0001137	Alternating esotropia
HP:0001492	Axenfeld anomaly
HP:0003593	Infantile onset
HP:0007663	Reduced visual acuity
HP:0007750	Hypoplasia of the fovea
HP:0008001	Foveal hyperpigmentation
HP:0025551	Optic nerve misrouting

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004097_3	Response to platinum-based neoadjuvant chemotherapy in cervical cancer	3.000000e-06
GCST007205_2	Schizophrenia	6.000000e-10
GCST010050_8	Adiponectin levels	8.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007943	response to platinum-based neoadjuvant chemotherapy
EFO:0004502	adiponectin measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
C563774	Foveal Hypoplasia and Anterior Segment Dysgenesis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — Orphan SLC38 transporters

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
2-palmitoylglycerol	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Methapyrilene	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

22 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00999609	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis
NCT06891443	PHASE3	RECRUITING	Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)
NCT00516477	PHASE1	COMPLETED	Safety Study in Subjects With Leber Congenital Amaurosis
NCT00821340	PHASE1	COMPLETED	Clinical Trial of Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations
NCT03913143	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Efficacy, Safety, Tolerability and Exposure After a Repeat-dose of Sepofarsen (QR-110) in LCA10 (ILLUMINATE)
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT00749957	PHASE1/PHASE2	COMPLETED	Phase 1/2 Safety and Efficacy Study of AAV-RPE65 Vector to Treat Leber Congenital Amaurosis
NCT01208389	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Phase 1 Follow-on Study of AAV2-hRPE65v2 Vector in Subjects With Leber Congenital Amaurosis (LCA) 2
NCT01496040	PHASE1/PHASE2	COMPLETED	Clinical Gene Therapy Protocol for the Treatment of Retinal Dystrophy Caused by Defects in RPE65
NCT02781480	PHASE1/PHASE2	COMPLETED	Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA)
NCT03913130	PHASE1/PHASE2	TERMINATED	Extension Study to Study PQ-110-001 (NCT03140969)
NCT03920007	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of Subretinally Injected ATSN-101 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D
NCT05203939	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study to Assess the Safety and Efficacy of OCU400 for Retinitis Pigmentosa and Leber Congenital Amaurosis
NCT05906953	PHASE1/PHASE2	RECRUITING	Safety and Efficacy Trial of HG004 for Leber Congenital Amaurosis Related to Rpe65 Gene Mutations (STAR)
NCT06088992	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Leber Congenital Amaurosis Inherited Blindness of Gene Therapy Trial(LIGHT)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT02575430	Not specified	COMPLETED	Natural History Study in Inherited Retinal Disease Subjects Caused by Mutations in RPE65 or LRAT
NCT02714816	Not specified	COMPLETED	Natural History Study of Patients With Leber Congenital Amaurosis Associated With Mutations in RPE65
NCT02946879	Not specified	COMPLETED	Long-Term Follow-Up Gene Therapy Study for Leber Congenital Amaurosis OPTIRPE65 (Retinal Dystrophy Associated With Defects in RPE65)
NCT02970266	Not specified	COMPLETED	Genetic Decryption of Leber Congenital Amaurosis (LCA) in a Large Cohort of Independent Families.
NCT07026565	Not specified	NOT_YET_RECRUITING	Psychotherapy Group for Parents of Children With LCA