SLC6A19

Summary

SLC6A19 (solute carrier family 6 member 19, HGNC:27960) is a protein-coding gene on chromosome 5p15.33, encoding Sodium-dependent neutral amino acid transporter B(0)AT1 (Q695T7). Transporter that mediates resorption of neutral amino acids across the apical membrane of renal and intestinal epithelial cells.

This gene encodes a system B(0) transmembrane protein that actively transports most neutral amino acids across the apical membrane of epithelial cells. Mutations in this gene may result in Hartnup disorder, an inherited disease with symptoms such as pellagra, cerebellar ataxia, and psychosis. The expression and function of B0AT1 (SLC6A19) in intestinal cells depends on the presence of the accessory protein angiotensin-converting enzyme 2 (ACE2) which, among other functions, acts as a chaperone for membrane trafficking of B0AT1. The ACE2 is also the cellular receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV) and for SARS-CoV-2 that is causing the coronavirus 2019 (COVID-19) pandemic

Source: NCBI Gene 340024 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Hartnup disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 586 total — 11 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 45
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001003841

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27960
Approved symbol	SLC6A19
Name	solute carrier family 6 member 19
Location	5p15.33
Locus type	gene with protein product
Status	Approved
Aliases	B0AT1
Ensembl gene	ENSG00000174358
Ensembl biotype	protein_coding
OMIM	608893
Entrez	340024

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 nonsense_mediated_decay

ENST00000304460, ENST00000515652

RefSeq mRNA: 1 — MANE Select: NM_001003841 NM_001003841

CCDS: CCDS34130

Canonical transcript exons

ENST00000304460 — 12 exons

Exon	Start	End
ENSE00001305783	1210444	1210581
ENSE00001307334	1201595	1201852
ENSE00001324241	1208746	1208886
ENSE00001329821	1216789	1216945
ENSE00001413056	1221701	1225111
ENSE00001493084	1216558	1216686
ENSE00003463840	1219505	1219664
ENSE00003476205	1213953	1214065
ENSE00003521835	1212303	1212484
ENSE00003562719	1213463	1213573
ENSE00003634864	1221151	1221313
ENSE00003644305	1218903	1219107

Expression profiles

Bgee: expression breadth broad, 67 present calls, max score 99.81.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.8816 / max 935.8354, expressed in 127 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55544	1.4579	66
55541	0.2655	71
55540	0.1023	42
55539	0.0267	12
55542	0.0171	7
55545	0.0044	2
55543	0.0043	3
55538	0.0035	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.81	gold quality
kidney epithelium	UBERON:0004819	99.61	gold quality
jejunal mucosa	UBERON:0000399	97.92	gold quality
duodenum	UBERON:0002114	95.91	gold quality
adult organism	UBERON:0007023	89.37	gold quality
adult mammalian kidney	UBERON:0000082	88.21	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.14	gold quality
small intestine	UBERON:0002108	86.94	gold quality
kidney	UBERON:0002113	83.77	gold quality
upper arm skin	UBERON:0004263	82.52	gold quality
jejunum	UBERON:0002115	81.60	gold quality
cardiac muscle of right atrium	UBERON:0003379	78.18	gold quality
left ventricle myocardium	UBERON:0006566	77.86	gold quality
gingival epithelium	UBERON:0001949	77.73	gold quality
epithelial cell of pancreas	CL:0000083	77.31	silver quality
renal medulla	UBERON:0000362	77.06	gold quality
pancreatic ductal cell	CL:0002079	76.92	silver quality
oocyte	CL:0000023	75.93	gold quality
secondary oocyte	CL:0000655	75.78	gold quality
superficial temporal artery	UBERON:0001614	75.34	gold quality
rectum	UBERON:0001052	75.27	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	74.26	gold quality
lower lobe of lung	UBERON:0008949	73.58	silver quality
endothelial cell	CL:0000115	72.32	gold quality
nasal cavity epithelium	UBERON:0005384	72.17	gold quality
myocardium	UBERON:0002349	72.09	gold quality
gingiva	UBERON:0001828	71.70	gold quality
colonic mucosa	UBERON:0000317	71.62	gold quality
gall bladder	UBERON:0002110	71.59	gold quality
quadriceps femoris	UBERON:0001377	70.10	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	69.01
E-ANND-3	yes	11.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, HNF1A, HNF4A, SOX9

miRNA regulators (miRDB)

69 targeting SLC6A19, 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-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-4666A-5P	99.41	69.72	1887

Literature-anchored findings (GeneRIF, showing 15)

• We identified six mutations in SLC6A19 that cosegregated with disease in the predicted recessive manner, with most affected individuals being compound heterozygotes. (PMID:15286788)
• One mutation, the D173N allele, is present in 42% of Hartnup chromosomes from apparently unrelated families from both Australia and North America. (PMID:17555458)
• Hartnup disorder is allelically heterogeneous with two mutated SLC6A19 allele. (PMID:18484095)
• These findings suggest that the rare SLC6A19-MS7 allele may be a risk factor for hypertension. (PMID:18671945)
• Suggest that amino acid transporters B(0)AT1 and b(0,+)AT are involved in the reabsorption of L-citrulline in the kidney, at least in part, by mediating the apical membrane transport of L-citrulline in renal tubule cells. (PMID:19322909)
• novel homozygous mutation of G284R in the transmembrane domain of the SLC6A19 transporter found in the proband, with typical dermatologic and neurologic manifestations and increased levels of urinary neutral amino acids (PMID:19335424)
• A novel SLC6A19 gene mutation is associated with late-onset seizures in a Korean patient with Hartnup disorder. (PMID:20399395)
• Average loss of solute carrier expression was similar in acute tubular necrosis (77%) and T cell-mediated rejection (75%) with high correlation of individual transcripts. (PMID:20883558)
• JAK2 up-regulates SLC6A19 activity which may foster amino acid uptake into JAK2 expressing cells. (PMID:21964291)
• PKB/Akt up-regulates SLC6A19 activity, which may foster amino acid uptake into PKB/Akt-expressing epithelial and tumor cells. (PMID:23234856)
• SIT1, B(0)AT1 and ACE2 were co-localized in the brush-border membrane of small intestine enterocytes. (PMID:25534429)
• discovered a heterozygous missense mutation (c700G to A [pG234S) in the SLC6A1 encoding GABA transporter 1 (PMID:31176687)
• The ACE2-B0AT1 complex exists as a dimer of heterodimers. Structural alignment of the RBD-ACE2-B0AT1 ternary complex with the S protein of SARS-CoV-2 suggests that two S protein trimers can simultaneously bind to an ACE2 homodimer. (PMID:32132184)
• Unraveling the Role of ACE2, the Binding Receptor for SARS-CoV-2, in Inflammatory Bowel Disease. (PMID:33064147)
• Functional characterization of sodium-coupled neutral “amino acid transport system B” in apical brush border membrane of an intact intestinal cell. (PMID:7876094)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc6a19a.1	ENSDARG00000018621
danio_rerio	slc6a19b	ENSDARG00000056719
danio_rerio	slc6a19a.2	ENSDARG00000091560
mus_musculus	Slc6a19	ENSMUSG00000021565
rattus_norvegicus	Slc6a19	ENSRNOG00000026501

Paralogs (19): SLC6A13 (ENSG00000010379), SLC6A7 (ENSG00000011083), SLC6A16 (ENSG00000063127), SLC6A15 (ENSG00000072041), SLC6A2 (ENSG00000103546), SLC6A4 (ENSG00000108576), SLC6A12 (ENSG00000111181), SLC6A8 (ENSG00000130821), SLC6A6 (ENSG00000131389), SLC6A11 (ENSG00000132164), SLC6A3 (ENSG00000142319), SLC6A1 (ENSG00000157103), SLC6A20 (ENSG00000163817), SLC6A18 (ENSG00000164363), SLC6A5 (ENSG00000165970), SLC6A9 (ENSG00000196517), SLC6A17 (ENSG00000197106), SLC6A14 (ENSG00000268104), (ENSG00000273554)

Protein

Protein identifiers

Sodium-dependent neutral amino acid transporter B(0)AT1 — Q695T7 (reviewed: Q695T7)

Alternative names: Solute carrier family 6 member 19, System B(0) neutral amino acid transporter AT1

All UniProt accessions (2): Q695T7, E9PD72

UniProt curated annotations — full annotation on UniProt →

Function. Transporter that mediates resorption of neutral amino acids across the apical membrane of renal and intestinal epithelial cells. This uptake is sodium-dependent and chloride-independent. Requires CLTRN in kidney or ACE2 in intestine for cell surface expression and amino acid transporter activity.

Subunit / interactions. Interacts in a tissue-specific manner with ACE2 in small intestine and with CLTRN in the kidney. Interacts with CLTRN; this interaction is required for trafficking of SLC6A19 to the plasma membrane and for its catalytic activation in kidneys. Interacts with ACE2; this interaction is required for trafficking of SLC6A19 to the plasma membrane and for its catalytic activation in intestine. Interacts with ANPEP; the interaction positively regulates its amino acid transporter activity.

Subcellular location. Cell membrane. Apical cell membrane.

Tissue specificity. Robust expression in kidney and small intestine, with minimal expression in pancreas. Also expressed in stomach, liver, duodenum, ileocecum, colon and prostate. Not detected in testis, whole brain, cerebellum, fetal liver, spleen, skeletal muscle, uterus, heart or lung.

Disease relevance. Hartnup disorder (HND) [MIM:234500] Autosomal recessive abnormality of renal and gastrointestinal neutral amino acid transport noted for its clinical variability. First described in 1956, HND is characterized by increases in the urinary and intestinal excretion of neutral amino acids. Individuals with typical Hartnup aminoaciduria may be asymptomatic, some develop a photosensitive pellagra-like rash, attacks of cerebellar ataxia and other neurological or psychiatric features. Although the definition of HND was originally based on clinical and biochemical abnormalities, its marked clinical heterogeneity has led to it being known as a disorder with a consistent pathognomonic neutral hyperaminoaciduria. The disease is caused by variants affecting the gene represented in this entry. Hyperglycinuria (HGLY) [MIM:138500] A condition characterized by excess of glycine in the urine. In some cases it is associated with renal colic and renal oxalate stones. The disease may be caused by variants affecting the gene represented in this entry. SLC6A19 deficiency combined with haploinsufficiency of SLC6A20 or partially inactivating mutations in SLC36A2, can be responsible for hyperglycinuria. Iminoglycinuria (IG) [MIM:242600] A disorder of renal tubular reabsorption of glycine and imino acids (proline and hydroxyproline), marked by excessive levels of all three substances in the urine. The disease may be caused by variants affecting the gene represented in this entry. SLC6A19 deficiency combined with haploinsufficiency of SLC6A20 or partially inactivating mutations in SLC36A2, can be responsible for iminoglycinuria. Additional polymorphisms and mutations in SLC6A18 can contribute to the IG phenotype in some families.

Similarity. Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A19 subfamily.

RefSeq proteins (1): NP_001003841* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000175	Na/ntran_symport	Family
IPR002438	Neutral_aa_SLC6	Family
IPR037272	SNS_sf	Homologous_superfamily

Pfam: PF00209

Catalyzed reactions (Rhea), 12 shown:

• L-leucine(in) + Na(+)(in) = L-leucine(out) + Na(+)(out) (RHEA:29263)
• L-valine(in) + Na(+)(in) = L-valine(out) + Na(+)(out) (RHEA:29267)
• L-isoleucine(in) + Na(+)(in) = L-isoleucine(out) + Na(+)(out) (RHEA:29275)
• L-alanine(in) + Na(+)(in) = L-alanine(out) + Na(+)(out) (RHEA:29283)
• L-serine(in) + Na(+)(in) = L-serine(out) + Na(+)(out) (RHEA:29575)
• glycine(in) + Na(+)(in) = glycine(out) + Na(+)(out) (RHEA:68228)
• L-cysteine(in) + Na(+)(in) = L-cysteine(out) + Na(+)(out) (RHEA:68232)
• L-glutamine(in) + Na(+)(in) = L-glutamine(out) + Na(+)(out) (RHEA:68236)
• L-methionine(in) + Na(+)(in) = L-methionine(out) + Na(+)(out) (RHEA:68240)
• L-phenylalanine(in) + Na(+)(in) = L-phenylalanine(out) + Na(+)(out) (RHEA:68244)
• L-tyrosine(in) + Na(+)(in) = L-tyrosine(out) + Na(+)(out) (RHEA:68248)
• L-tryptophan(in) + Na(+)(in) = L-tryptophan(out) + Na(+)(out) (RHEA:68252)

UniProt features (111 total): helix 31, strand 18, sequence variant 16, topological domain 13, turn 13, transmembrane region 12, glycosylation site 5, modified residue 2, chain 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
9KXW	ELECTRON MICROSCOPY	2.66
9KY0	ELECTRON MICROSCOPY	2.68
9KXT	ELECTRON MICROSCOPY	2.7
9KXV	ELECTRON MICROSCOPY	2.71
9KXX	ELECTRON MICROSCOPY	2.77
9KXZ	ELECTRON MICROSCOPY	2.8
9KY1	ELECTRON MICROSCOPY	2.8
9KXY	ELECTRON MICROSCOPY	2.82
9KXU	ELECTRON MICROSCOPY	2.87
9VA2	ELECTRON MICROSCOPY	2.87
6M17	ELECTRON MICROSCOPY	2.9
6M18	ELECTRON MICROSCOPY	2.9
8I93	ELECTRON MICROSCOPY	3.1
9LSZ	ELECTRON MICROSCOPY	3.11
8WBY	ELECTRON MICROSCOPY	3.18
7V61	ELECTRON MICROSCOPY	3.2
8I92	ELECTRON MICROSCOPY	3.2
8WBZ	ELECTRON MICROSCOPY	3.2
9VA1	ELECTRON MICROSCOPY	3.24
6M1D	ELECTRON MICROSCOPY	4.5
7DWX	ELECTRON MICROSCOPY	8.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q695T7-F1	90.20	0.75

Antibody-complex structures (SAbDab): 1 — 7V61

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 17, 627

Glycosylation sites (5): 158, 182, 258, 354, 368

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-352230	Amino acid transport across the plasma membrane
R-HSA-442660	SLC-mediated transport of neurotransmitters
R-HSA-5619044	Defective transport of neurotransmitters by SLC6A19 causes Hartnup disorder (HND)
R-HSA-5659735	Defective transport of amino acids by SLC6A19 causes Hartnup disorder (HND)
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-425366
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters

MSigDB gene sets: 202 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_AMINO_ACID_TRANSPORT, NIKOLSKY_BREAST_CANCER_5P15_AMPLICON, GOBP_VIRAL_LIFE_CYCLE, GOCC_APICAL_PLASMA_MEMBRANE, SABATES_COLORECTAL_ADENOMA_DN, GOBP_IMPORT_INTO_CELL, GOBP_RESPONSE_TO_NUTRIENT, GOBP_NEUTRAL_AMINO_ACID_TRANSPORT, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_SODIUM_ION_TRANSPORT

GO Biological Process (7): amino acid transport (GO:0006865), response to nutrient (GO:0007584), neutral amino acid transport (GO:0015804), viral life cycle (GO:0019058), sodium ion transmembrane transport (GO:0035725), amino acid transmembrane transport (GO:0003333), transmembrane transport (GO:0055085)

GO Molecular Function (6): amino acid transmembrane transporter activity (GO:0015171), neutral L-amino acid transmembrane transporter activity (GO:0015175), symporter activity (GO:0015293), protein binding (GO:0005515), transmembrane transporter activity (GO:0022857), metal ion binding (GO:0046872)

GO Cellular Component (5): plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), brush border membrane (GO:0031526), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
SLC transporter disorders	2
SLC-mediated transport of amino acids	1
SLC-mediated transmembrane transport	1
Transport of small molecules	1
Disorders of transmembrane transporters	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
amino acid transport	2
transmembrane transport	2
response to nutrient levels	1
response to chemical	1
viral process	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
cellular process	1
amino acid transmembrane transport	1
transmembrane transporter activity	1
amino acid transmembrane transporter activity	1
neutral amino acid transport	1
secondary active transmembrane transporter activity	1
binding	1
transporter activity	1
cation binding	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
brush border	1
apical plasma membrane	1
cell projection membrane	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

956 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC6A19	ACE2	Q9BYF1	996
SLC6A19	SLC36A2	Q495M3	956
SLC6A19	CLTRN	Q9HBJ8	952
SLC6A19	SLC7A9	P82251	748
SLC6A19	SLC1A5	Q15758	716
SLC6A19	ACE	P12821	699
SLC6A19	SLC3A2	P08195	687
SLC6A19	SLC3A1	Q07837	685
SLC6A19	SLC1A1	P43005	670
SLC6A19	SLC7A7	Q9UM01	668
SLC6A19	SLC15A1	P46059	641
SLC6A19	SLC7A8	Q9UHI5	621
SLC6A19	SLC7A6	Q92536	609
SLC6A19	SLC43A2	Q8N370	604
SLC6A19	TMPRSS2	O15393	595

IntAct

6 interactions, top by confidence:

A	B	Type	Score
ACE2	S	psi-mi:“MI:0915”(physical association)	1.000
ACE2	SLC6A19	psi-mi:“MI:0915”(physical association)	0.640
SLC6A19	TMEM129	psi-mi:“MI:0914”(association)	0.350

BioGRID (13): SLC6A19 (Co-crystal Structure), SLC6A19 (Reconstituted Complex), SLC6A19 (Co-crystal Structure), SLC6A19 (Co-purification), SLC6A19 (Affinity Capture-Western), SLC6A19 (Affinity Capture-Western), SLC6A19 (Co-fractionation), ATE1 (Affinity Capture-MS), TMEM27 (Affinity Capture-MS), GALNT7 (Affinity Capture-MS), TM9SF3 (Affinity Capture-MS), TMEM129 (Affinity Capture-MS), TMEM186 (Affinity Capture-MS)

ESM2 similar proteins: A0A2K1ZPK4, B3MRS1, B4L7U0, B4NDL8, B9GNS0, B9NAE4, D3ZIS0, O49423, O64759, O77741, P23978, P30531, P31636, P31637, P31648, P38778, P38925, P48057, P49283, P51905, P53793, P53794, P65544, P65545, Q10177, Q10Q65, Q12078, Q21433, Q21434, Q2QN30, Q5R6J1, Q67UC7, Q695T7, Q6YSA9, Q6ZG85, Q84YJ9, Q869V1, Q8UEM1, Q91ZP4, Q92BT1

Diamond homologs: A5PJX7, A7Y2W8, A7Y2X0, B3MRS1, B3NV41, B4GVM9, B4JMC1, B4L7U0, B4MEG2, B4NDL8, B4PZQ4, B4R4T6, G5EBN9, O18875, O35316, O35899, O45813, O55192, O76689, O88575, O88576, P23975, P23977, P23978, P27799, P27922, P28570, P28571, P28572, P28573, P30531, P31641, P31643, P31645, P31646, P31647, P31648, P31649, P31650, P31651

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	27
Uncertain significance	262
Likely benign	198
Benign	42

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2018	NM_001003841.3(SLC6A19):c.884_885del (p.Val295fs)	Pathogenic
2020	NM_001003841.3(SLC6A19):c.718C>T (p.Arg240Ter)	Pathogenic
2077836	NM_001003841.3(SLC6A19):c.1341_1342del (p.Arg447fs)	Pathogenic
2088953	NM_001003841.3(SLC6A19):c.1297_1300del (p.Phe433fs)	Pathogenic
2169290	NM_001003841.3(SLC6A19):c.167G>A (p.Trp56Ter)	Pathogenic
3627640	NM_001003841.3(SLC6A19):c.587G>A (p.Trp196Ter)	Pathogenic
449553	NM_001003841.3(SLC6A19):c.1173+2T>G	Pathogenic
4724115	NM_001003841.3(SLC6A19):c.810del (p.Asp270fs)	Pathogenic
591734	NM_001003841.3(SLC6A19):c.728del (p.Thr243fs)	Pathogenic
916044	NM_001003841.3(SLC6A19):c.1787_1788insG (p.Ile597fs)	Pathogenic
917714	NM_001003841.3(SLC6A19):c.532C>T (p.Arg178Ter)	Pathogenic
1174952	NM_001003841.3(SLC6A19):c.774+1G>A	Likely pathogenic
1482366	NM_001003841.3(SLC6A19):c.277G>A (p.Gly93Arg)	Likely pathogenic
1705051	NM_001003841.3(SLC6A19):c.1550A>G (p.Asp517Gly)	Likely pathogenic
2430279	NM_001003841.3(SLC6A19):c.170G>A (p.Arg57His)	Likely pathogenic
2431061	NM_001003841.3(SLC6A19):c.311G>A (p.Trp104Ter)	Likely pathogenic
2500902	NM_001003841.3(SLC6A19):c.1169C>G (p.Ser390Ter)	Likely pathogenic
2585140	NM_001003841.3(SLC6A19):c.774+2T>G	Likely pathogenic
2977105	NM_001003841.3(SLC6A19):c.664-1G>A	Likely pathogenic
3591604	NM_001003841.3(SLC6A19):c.522C>A (p.Tyr174Ter)	Likely pathogenic
3591607	NM_001003841.3(SLC6A19):c.609_610insA (p.Ala204fs)	Likely pathogenic
3591621	NM_001003841.3(SLC6A19):c.774+1G>C	Likely pathogenic
3591624	NM_001003841.3(SLC6A19):c.834dup (p.Phe279fs)	Likely pathogenic
3591635	NM_001003841.3(SLC6A19):c.1125C>A (p.Tyr375Ter)	Likely pathogenic
3591636	NM_001003841.3(SLC6A19):c.1125C>G (p.Tyr375Ter)	Likely pathogenic
3591649	NM_001003841.3(SLC6A19):c.1358G>A (p.Trp453Ter)	Likely pathogenic
3591653	NM_001003841.3(SLC6A19):c.1435C>T (p.Gln479Ter)	Likely pathogenic
3591660	NM_001003841.3(SLC6A19):c.1589G>A (p.Trp530Ter)	Likely pathogenic
3591662	NM_001003841.3(SLC6A19):c.1601G>A (p.Trp534Ter)	Likely pathogenic
3591663	NM_001003841.3(SLC6A19):c.1602G>A (p.Trp534Ter)	Likely pathogenic

SpliceAI

2257 predictions. Top by Δscore:

Variant	Effect	Δscore
5:1201850:G:GT	donor_gain	1.0000
5:1212301:AG:A	acceptor_gain	1.0000
5:1212302:G:A	acceptor_gain	1.0000
5:1212481:G:GT	donor_gain	1.0000
5:1212481:G:T	donor_gain	1.0000
5:1212482:A:T	donor_gain	1.0000
5:1212483:AG:A	donor_loss	1.0000
5:1212485:G:T	donor_loss	1.0000
5:1212486:T:G	donor_loss	1.0000
5:1213462:GGCC:G	acceptor_gain	1.0000
5:1213569:CCAAC:C	donor_gain	1.0000
5:1213570:CAAC:C	donor_gain	1.0000
5:1213571:AAC:A	donor_gain	1.0000
5:1213572:AC:A	donor_gain	1.0000
5:1213573:CGTAA:C	donor_loss	1.0000
5:1213574:G:GG	donor_gain	1.0000
5:1213575:TAAG:T	donor_loss	1.0000
5:1214061:GTGCA:G	donor_gain	1.0000
5:1214062:TGCA:T	donor_gain	1.0000
5:1214063:GCA:G	donor_gain	1.0000
5:1214063:GCAG:G	donor_gain	1.0000
5:1214066:G:GG	donor_gain	1.0000
5:1216556:A:AG	acceptor_gain	1.0000
5:1216557:G:GG	acceptor_gain	1.0000
5:1216683:GCAC:G	donor_gain	1.0000
5:1216687:G:GG	donor_gain	1.0000
5:1216943:GAG:G	donor_gain	1.0000
5:1216944:AGG:A	donor_loss	1.0000
5:1216945:GGTA:G	donor_loss	1.0000
5:1216946:G:GG	donor_gain	1.0000

AlphaMissense

4152 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:1201755:G:C	W35C	0.996
5:1201755:G:T	W35C	0.996
5:1221224:A:C	S538R	0.996
5:1221226:C:A	S538R	0.996
5:1221226:C:G	S538R	0.996
5:1208820:G:T	G93W	0.995
5:1208821:G:A	G93E	0.994
5:1221212:T:A	W534R	0.994
5:1221212:T:C	W534R	0.994
5:1201753:T:A	W35R	0.993
5:1201753:T:C	W35R	0.993
5:1208853:T:A	W104R	0.993
5:1208853:T:C	W104R	0.993
5:1208825:G:C	Q94H	0.992
5:1208825:G:T	Q94H	0.992
5:1214049:A:C	S291R	0.992
5:1214051:C:A	S291R	0.992
5:1214051:C:G	S291R	0.992
5:1208815:C:A	A91D	0.991
5:1212434:T:A	W205R	0.991
5:1212434:T:C	W205R	0.991
5:1214029:G:A	G284E	0.991
5:1208821:G:T	G93V	0.990
5:1213980:T:A	W268R	0.990
5:1213980:T:C	W268R	0.990
5:1208751:T:C	F70L	0.989
5:1208753:C:A	F70L	0.989
5:1208753:C:G	F70L	0.989
5:1208820:G:A	G93R	0.989
5:1208820:G:C	G93R	0.989

dbSNP variants (sampled 300 via entrez): RS1000153569 (5:1205120 G>A,C), RS1000166102 (5:1222026 A>G,T), RS1000236093 (5:1206201 C>T), RS1000266201 (5:1206624 G>A), RS1000603919 (5:1222848 G>C), RS1000678424 (5:1223907 C>T), RS1000794728 (5:1219080 C>G,T), RS1000850405 (5:1214920 C>G,T), RS1000899104 (5:1223550 A>G), RS1000996420 (5:1218644 C>T), RS1001057989 (5:1222716 C>A,T), RS1001110564 (5:1218825 A>G,T), RS1001122805 (5:1207298 C>T), RS1001535737 (5:1207223 C>A,T), RS1001592827 (5:1202760 A>G)

Disease associations

OMIM: gene MIM:608893 | disease phenotypes: MIM:234500, MIM:138500, MIM:242600, MIM:613989

GenCC curated gene-disease

Disease	Classification	Inheritance
Hartnup disease	Definitive	Autosomal recessive
hyperglycinuria	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Hartnup disease	Definitive	AR

Mondo (6): Hartnup disease (MONDO:0009324), hyperglycinuria (MONDO:0007677), iminoglycinuria (MONDO:0009448), dyskeratosis congenita, autosomal dominant 2 (MONDO:0013521), idiopathic pulmonary fibrosis (MONDO:0800504), intellectual disability (MONDO:0001071)

Orphanet (4): Hartnup disease (Orphanet:2116), Iminoglycinuria (Orphanet:42062), Idiopathic pulmonary fibrosis (Orphanet:2032), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000206	Glossitis
HP:0000230	Gingivitis
HP:0000486	Strabismus
HP:0000504	Abnormality of vision
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000709	Psychosis
HP:0000712	Emotional lability
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000988	Skin rash
HP:0000992	Cutaneous photosensitivity
HP:0001053	Hypopigmented skin patches
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0002024	Malabsorption
HP:0002076	Migraine
HP:0002131	Episodic ataxia
HP:0002154	Hyperglycinemia
HP:0002353	EEG abnormality
HP:0002383	Infectious encephalitis

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002553_8	Pancreatic cancer	1.000000e-13
GCST003119_4	Urinary metabolites	2.000000e-26
GCST009733_109	Urinary metabolite levels in chronic kidney disease	5.000000e-23
GCST009733_110	Urinary metabolite levels in chronic kidney disease	1.000000e-16
GCST009733_148	Urinary metabolite levels in chronic kidney disease	1.000000e-15
GCST009733_38	Urinary metabolite levels in chronic kidney disease	9.000000e-16
GCST009733_94	Urinary metabolite levels in chronic kidney disease	2.000000e-15
GCST010559_1	Urine 6-bromotryptophan levels in chronic kidney disease	6.000000e-12
GCST012020_607	Serum metabolite levels	2.000000e-20
GCST012021_5	Serum metabolite levels	2.000000e-20

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D006250	Hartnup Disease	C10.228.140.163.100.355; C12.050.351.968.419.815.885.625; C12.200.777.419.815.885.457; C12.950.419.815.885.625; C16.320.565.151.355; C16.320.565.189.355; C16.320.831.885.457; C18.452.132.100.355; C18.452.648.151.355; C18.452.648.189.355
D054990	Idiopathic Pulmonary Fibrosis	C08.381.483.652.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C563009	Glycinuria with or without Oxalate Urolithiasis (supp.)
C536285	Iminoglycinuria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724588 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,215 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL93233	CINROMIDE	2	1,215

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Neutral amino acid transporter subfamily

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
cinromide	Inhibition	6.4	pIC50
inhibitor E18	Inhibition	5.47	pIC50
inhibitor CB3	Inhibition	5.31	pIC50
inhibitor E4	Inhibition	5.11	pIC50
nimesulide	Inhibition	4.64	pIC50
benzatropine	Inhibition	4.36	pIC50

ChEMBL bioactivities

9 potent at pChembl≥5 of 9 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.52	IC50	3	nM	CHEMBL6173546
8.40	IC50	4	nM	CHEMBL6176097
8.40	IC50	4	nM	CHEMBL6162956
8.30	IC50	5	nM	CHEMBL6174568
8.30	IC50	5	nM	CHEMBL6169626
8.30	IC50	5	nM	CHEMBL6164327
6.55	IC50	280	nM	CINROMIDE
6.43	IC50	370	nM	CINROMIDE
6.30	IC50	500	nM	CINROMIDE

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation	2
bisphenol A	affects cotreatment, increases methylation	1
2,3,4,5-tetrachlorophenate	affects response to substance	1
abrine	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Angiotensin-Converting Enzyme Inhibitors	increases expression	1
Arsenic	affects methylation	1
Hydrogen Peroxide	increases expression	1
Niclosamide	decreases expression	1
Phthalic Acids	decreases methylation	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	affects methylation	1

ChEMBL screening assays

4 unique, capped per target: 3 functional, 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5723520	Functional	Affinity On-target Cellular interaction: (Fluorescence imaging plate reader (FLIPR) membrane potential (FMP) assay, MDCK cells) EUB0002537a SLC6A19	Affinity On-target Cellular Literature for EUbOPEN Chemogenomic Library
CHEMBL6141220	Binding	Inhibition of human SLC6A19 expressed in MDCK cells co-expressing human TMEM27 using 13C6/15N-L-Isoleucine as substrate preincubated for 20 mins followed by substrate addition and measured after 20 mins by stable isotope uptake assay	Novel Substituted Cyclic Compounds as SLC6A19 Inhibitors for Treating Phenylketonuria and Other Amino Acidurias. — ACS Med Chem Lett

Cellosaurus cell lines

4 cell lines: 2 finite cell line, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_AA45	GM05003	Finite cell line	Male
CVCL_AA46	GM05004	Finite cell line	Male
CVCL_D4UD	HuH7-SLC6A19-KO-c10	Cancer cell line	Male
CVCL_D4UE	HuH7-SLC6A19-KO-c7	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00637065	PHASE4	UNKNOWN	Bosentan in Pulmonary Hypertension in Interstitial Lung Disease Treatment Study
NCT01321996	PHASE4	TERMINATED	68Ga-DOTA-NOC PET/CT in Patients With Idiopathic Pulmonary Fibrosis
NCT01382368	PHASE4	UNKNOWN	Acute Effect of Sildenafil on Exercise Tolerance and Functional Capacity in COPD, IPF and Post Pneumonectomy Patients
NCT02579603	PHASE4	COMPLETED	Safety, Tolerability and PK of Nintedanib in Combination With Pirfenidone in IPF
NCT02598193	PHASE4	COMPLETED	Safety and Tolerability Study of Pirfenidone in Combination With Nintedanib in Participants With Idiopathic Pulmonary Fibrosis (IPF)
NCT02606877	PHASE4	COMPLETED	A Study to Compare the Amount of Nintedanib and Pirfenidone in the Blood When Nintedanib and Pirfenidone Are Given Separately or in Combination
NCT02788474	PHASE4	COMPLETED	Effect of Nintedanib on Biomarkers of Extracellular Matrix Turnover in Patients With Idiopathic Pulmonary Fibrosis and Limited Forced Vital Capacity Impairment
NCT03503188	PHASE4	COMPLETED	Digital Auscultation Test - IPF Data Collection
NCT03717012	PHASE4	TERMINATED	Study of Pulmonary Rehabilitation in Patients With Idiopathic Pulmonary Fibrosis (IPF)
NCT03939520	PHASE4	COMPLETED	Management of Progressive Disease in Idiopathic Pulmonary Fibrosis
NCT00047645	PHASE3	COMPLETED	A Study of the Safety and Efficacy Interferon-Gamma 1b in Patients With Idiopathic Pulmonary Fibrosis (IPF)
NCT00075998	PHASE3	TERMINATED	The INSPIRE Trial: A Study of Interferon Gamma-1b for Idiopathic Pulmonary Fibrosis (IPF)
NCT00076635	PHASE3	TERMINATED	An Open-Label Study of the Safety of Interferon Gamma-1b in Patients With IPF
NCT00105183	PHASE3	COMPLETED	EZ-2053 in the Prophylaxis of Acute Pulmonary Allograft Rejection
NCT00203697	PHASE3	UNKNOWN	Minocycline Therapy for Lung Scarring in Patients With Idiopathic Pulmonary Fibrosis - a Pilot Study
NCT00287716	PHASE3	COMPLETED	Three-Arm Study of the Safety and Efficacy of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis
NCT00287729	PHASE3	COMPLETED	Safety and Efficacy of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis
NCT00391443	PHASE3	COMPLETED	BUILD 3: Bosentan Use in Interstitial Lung Disease
NCT00600028	PHASE3	COMPLETED	Treatment of Chronic Cough in Idiopathic Pulmonary Fibrosis With Thalidomide
NCT00631475	PHASE3	COMPLETED	Open Label Extension Study in Patients With Idiopathic Pulmonary Fibrosis Who Completed Protocol AC-052-321/ BUILD 3 / NCT00391443
NCT00662038	PHASE3	COMPLETED	Open-Label Study of the Long Term Safety of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis (IPF)
NCT00768300	PHASE3	TERMINATED	(ARTEMIS-IPF) Randomized, Placebo-Controlled Study to Evaluate Safety and Effectiveness of Ambrisentan in IPF
NCT00879229	PHASE3	TERMINATED	ARTEMIS-PH - Study of Ambrisentan in Subjects With Pulmonary Hypertension Associated With Idiopathic Pulmonary Fibrosis
NCT00957242	PHASE3	TERMINATED	AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis
NCT01366209	PHASE3	COMPLETED	Efficacy and Safety of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis (IPF)
NCT01619085	PHASE3	COMPLETED	Extension Trial of the Long Term Safety of BIBF 1120 in Patients With Idiopathic Pulmonary Fibrosis
NCT01777737	PHASE3	TERMINATED	Study to Test the Validity of the Treatment of Idiopathic Pulmonary Fibrosis With Cotrimoxazole
NCT01979952	PHASE3	COMPLETED	Nintedanib Twice Daily vs Placebo in Patients Diagnosed With Idiopathic Pulmonary Fibrosis (IPF)
NCT02460588	PHASE3	COMPLETED	Cyclophosphamide for Acute Exacerbation of Idiopathic Pulmonary Fibrosis
NCT02739165	PHASE3	COMPLETED	Clinical Study of ART-123 for the Treatment of Acute Exacerbation of Idiopathic Pulmonary Fibrosis
NCT02759120	PHASE3	TERMINATED	CleanUP IPF for the Pulmonary Trials Cooperative
NCT02802345	PHASE3	COMPLETED	Efficacy and Safety of Nintedanib Co-administered With Sildenafil in Idiopathic Pulmonary Fibrosis Patients With Advanced Lung Function Impairment
NCT03208933	PHASE3	COMPLETED	Open-label Study to Assess the Effectiveness of Pirfenidone in Participants With Idiopathic Pulmonary Fibrosis (IPF).
NCT03711162	PHASE3	TERMINATED	A Clinical Study to Test How Effective and Safe GLPG1690 is for Subjects With Idiopathic Pulmonary Fibrosis (IPF) When Used Together With Standard of Care
NCT03733444	PHASE3	TERMINATED	A Clinical Study to Test How Effective and Safe GLPG1690 is for Participants With Idiopathic Pulmonary Fibrosis (IPF) When Used Together With Standard of Care
NCT03955146	PHASE3	TERMINATED	Zephyrus I: Evaluation of Efficacy and Safety of Pamrevlumab in Participants With Idiopathic Pulmonary Fibrosis (IPF)
NCT04300920	PHASE3	COMPLETED	Prospective Treatment Efficacy in IPF Using Genotype for Nac Selection (PRECISIONS) Trial
NCT04419558	PHASE3	TERMINATED	Zephyrus II: Efficacy and Safety Study of Pamrevlumab in Participants With Idiopathic Pulmonary Fibrosis (IPF)