SLC11A1

Summary

SLC11A1 (solute carrier family 11 member 1, HGNC:10907) is a protein-coding gene on chromosome 2q35, encoding Natural resistance-associated macrophage protein 1 (P49279). Macrophage-specific antiporter that fluxes metal ions in either direction against a proton gradient.

This gene is a member of the solute carrier family 11 (proton-coupled divalent metal ion transporters) family and encodes a multi-pass membrane protein. The protein functions as a divalent transition metal (iron and manganese) transporter involved in iron metabolism and host resistance to certain pathogens. Mutations in this gene have been associated with susceptibility to infectious diseases such as tuberculosis and leprosy, and inflammatory diseases such as rheumatoid arthritis and Crohn disease. Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only one has been determined.

Source: NCBI Gene 6556 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cystic fibrosis (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 136 total
• Phenotypes (HPO): 35
• Druggable target: yes
• MANE Select transcript: NM_000578

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10907
Approved symbol	SLC11A1
Name	solute carrier family 11 member 1
Location	2q35
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000018280
Ensembl biotype	protein_coding
OMIM	600266
Entrez	6556

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 13 retained_intron, 7 protein_coding, 5 nonsense_mediated_decay

ENST00000233202, ENST00000354352, ENST00000460592, ENST00000465984, ENST00000468221, ENST00000468721, ENST00000469449, ENST00000469799, ENST00000471875, ENST00000473367, ENST00000475225, ENST00000481524, ENST00000483487, ENST00000490536, ENST00000490872, ENST00000492413, ENST00000494322, ENST00000539932, ENST00000714041, ENST00000868333, ENST00000868334, ENST00000868335, ENST00000868336, ENST00000965608, ENST00000965609

RefSeq mRNA: 1 — MANE Select: NM_000578 NM_000578

CCDS: CCDS2415

Canonical transcript exons

ENST00000233202 — 15 exons

Exon	Start	End
ENSE00001850613	218394925	218396894
ENSE00003471197	218392981	218393130
ENSE00003479477	218387800	218387955
ENSE00003524403	218394632	218394785
ENSE00003538492	218387160	218387230
ENSE00003558844	218386635	218386741
ENSE00003571200	218382960	218383102
ENSE00003609872	218389870	218390028
ENSE00003616636	218387565	218387632
ENSE00003629465	218391198	218391287
ENSE00003665156	218394120	218394193
ENSE00004022603	218384243	218384365
ENSE00004022604	218382273	218382375
ENSE00004022605	218385147	218385266
ENSE00004022606	218391376	218391495

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 99.27.

FANTOM5 (CAGE): breadth broad, TPM avg 24.2097 / max 1968.1344, expressed in 411 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25324	12.9612	380
25323	5.0375	332
25325	3.3865	286
25326	1.2659	203
25322	0.5734	124
25321	0.3493	83
25327	0.3430	108
25328	0.2930	115

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	99.27	gold quality
upper lobe of left lung	UBERON:0008952	98.74	gold quality
granulocyte	CL:0000094	98.64	gold quality
monocyte	CL:0000576	98.48	gold quality
mononuclear cell	CL:0000842	98.10	gold quality
leukocyte	CL:0000738	97.99	gold quality
blood	UBERON:0000178	97.98	gold quality
upper lobe of lung	UBERON:0008948	97.47	gold quality
spleen	UBERON:0002106	95.60	gold quality
buccal mucosa cell	CL:0002336	94.42	gold quality
left uterine tube	UBERON:0001303	91.84	gold quality
left adrenal gland cortex	UBERON:0035825	91.45	gold quality
left adrenal gland	UBERON:0001234	91.32	gold quality
bone marrow cell	CL:0002092	90.90	gold quality
right adrenal gland cortex	UBERON:0035827	90.67	gold quality
right adrenal gland	UBERON:0001233	89.62	gold quality
adrenal cortex	UBERON:0001235	89.52	gold quality
diaphragm	UBERON:0001103	88.97	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	88.94	gold quality
omental fat pad	UBERON:0010414	88.86	gold quality
peritoneum	UBERON:0002358	88.80	gold quality
mucosa of stomach	UBERON:0001199	88.67	gold quality
bone marrow	UBERON:0002371	88.41	gold quality
adipose tissue of abdominal region	UBERON:0007808	87.59	gold quality
left coronary artery	UBERON:0001626	87.16	gold quality
tendon of biceps brachii	UBERON:0008188	87.15	silver quality
lung	UBERON:0002048	86.78	gold quality
spinal cord	UBERON:0002240	86.56	gold quality
descending thoracic aorta	UBERON:0002345	86.54	gold quality
right atrium auricular region	UBERON:0006631	86.39	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	2907.50
E-HCAD-15	yes	2072.46
E-MTAB-9221	yes	668.43
E-CURD-122	yes	72.78
E-GEOD-84465	yes	47.29
E-ANND-3	yes	34.58
E-GEOD-130148	yes	24.03
E-HCAD-25	yes	18.32
E-MTAB-8498	yes	10.97
E-MTAB-9801	yes	7.58

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF3, BATF, CEBPG, DNMT3B, E2F1, HIF1A, HOXC8, IRF8, JUN, MYC, RARA, SP1, ZBTB17, ZFP1, ZNF91

miRNA regulators (miRDB)

74 targeting SLC11A1, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-4530	99.69	66.47	1509

Literature-anchored findings (GeneRIF, showing 40)

• The data supports a role for NRAMP1 in the antimicrobial defenses of human neutrophils. (PMID:12070036)
• NRAMP1 gene promoter polymorphism could influence the radiological severity of rheumatoid arthritis and disease susceptibility, particularly in individuals lacking HLA-linked risk factors. (PMID:12135431)
• Study of the CTLA-4 gene and type 1 diabetes showed that the CTLA-4 gene significantly contributed to the development of type 1 diabetes, whereas NRAMP1 had an additional effect on the onset of type 1 diabetes in the young population. (PMID:12136340)
• results indicate that variant alleles in the Nramp1 gene are associated with increased mycobacterial replication rather than susceptibility for tuberculosis and may thus confer increased risk of severe disease (PMID:12195379)
• The 469 + 14 G/C (INT4), 1465 - 85 G/A, and C274T polymorphisms of NRAMP1 were analyzed in ethnic Russians with (N = 58) or without (N = 127) tuberculosis. On evidence of allele and genotype frequencies, none of the polymorphisms was associated with TB (PMID:12391841)
• associations/linkages of SLC11A1 with human disease and how these relate to functional promoter region polymorphisms (PMID:12527228)
• Role in susceptibility to Kawasaki disease. (PMID:12552460)
• Variations of the Nramp1 gene affects susceptibility to visceral leishmaniasis. (PMID:12618857)
• The NRAMP1 genetic polymorphisms were closely related to tuberculous pleurisy. (PMID:12729343)
• Polymorphisms of D543N and 3’UTR locus in NRAMP1 gene might affect their susceptibility to pulmonary tuberculosis in Chinese Han population. (PMID:14703493)
• Polymorphisms in the VDR and NRAMP1 gene are statistically associated with susceptibility to pulmonary tuberculosis in the Chinese Han population. (PMID:15141734)
• demonstrated significant differences in the ability of polymorphic alleles to regulate gene expression upon iron loading and addition of exogenous stimuli (PMID:15223010)
• no evidence of association between SLC11A1 polymorphisms and multiple sclerosis susceptibility in the Spanish population. (PMID:15584484)
• Existence of a locus at or near SLC11A1 that is a strong susceptibility factor for JIA in Finnish patients. (PMID:15641099)
• allele 3 of SLC11A1 at the functional promoter region repeat polymorphism was significantly associated with sarcoidosis (PMID:15702130)
• promoter polymorphism exhibited an interaction with the lepromin response, suggesting a susceptibility to leprosy (PMID:15755200)
• Lack of association of SLC11A1 as an inflammatory bowel disease candidate gene. (PMID:15757519)
• Genetic variants of NRAMP1 may have an effect on bacilli growth and on outcomes of pulmonary tuberculosis, but not on susceptibility to M. tuberculosis infection. (PMID:15825023)
• Genetic variation in both the promoter region and intron 1 of the SLC11A1 gene is associated with esophageal cancer susceptibility (PMID:15860357)
• Allele 2 associated with low SLC11A1 and protection against rheumatoid arthritis. Negative association of allele 2 with autoimmune type 1 diabetes suggests less active immune system in subjects with allele 2 may protect from autoimmune diseases. (PMID:15877293)
• NRAMP1 is not likely to be a major contributor to the genetic etiology of asthma and asthma-related phenotypes. (PMID:15988535)
• Iron dysregulation mediated by allelic effects of SLC11A1 may contribute to inflammatory bowel disease susceptibility. (PMID:16059695)
• NRAMP1 823C/1703G/1729+del 4 TGTG+ haplotype is associated with susceptibility to rheumatoid arthritis (PMID:16125248)
• Gene expression of SLC11A1 is regulated by HuR. (PMID:16135804)
• This work examined the polymorphism of the human NRAMP1 gene in 65 patients with brucellosis and 89 healthy controls and found no significant differences in the alleles studied. (PMID:16182589)
• A genetic polymorphism in the SLC11A1 gene plays a role in susceptibility to develop Buruli ulcer, with an estimated 13% population attributable risk. (PMID:16395392)
• We identified a novel trinucleotide (ATA)n repeat polymorphism in intron 8 of SLC11AI. We found no significant association between this marker and pulmonary TB. (PMID:16426236)
• Association between SLC11A1 and Tuberculosis, particularly to the common pulmonary form. (PMID:16461017)
• Genetic variation in NRAMP 1 may affect susceptibility to and increase risk for tuberculosis in Taiwanese aboriginals (PMID:16638645)
• An association was found between 3’-UTR polymorphisms of Slc11a1 and incidence of PTLD after liver transplantation. (PMID:16734634)
• Polymorphism of 3’UTR locus in NRAMP1 gene might affect their susceptibility to TB in Han nationality living in the northern part of China, and polymorphism of INT4 might affect the pathological characters of tuberculosis. (PMID:16737570)
• Polymorphisms at 3’ UTR and D543N loci had statistically significant association between the NRAMP1 variants and susceptibility to tuberculosis in the East-Asia descendants [meta-analysis] (PMID:16981342)
• The allele 3 and the genotype allele 3/allele 3 of the 5’-promoter (GT)n in the SLC11A1 gene may have a protective effect for the development of Behcet’s disease in the Korean population. (PMID:17062442)
• While Crohn’s disease was strongly associated with NRAMP1, NRAMP1 polymorphisms themselves were not correlated. (PMID:17131479)
• The SLC 11A1 274T 823C 1703G 1729+55 del 4 TGTG+ haplotype is associated with the development of reactive arthritis in Taiwan. (PMID:17211726)
• There is an increased risk of pulmonary tuberculosis in Chinese iron miners exposed to silica dust carrying both the NRAMP1 D543N G/G and NRAMP1 INT4 G/C+C/C genotypes. (PMID:17223386)
• The NRAMP1 genes are not associated with susceptibility to tuberculosis in Thais. (PMID:17298451)
• role SLC11A1 in linking infections, autoimmunity and cancer [review] (PMID:17378896)
• We conclude that the difference in SLC11A1 promoter polymorphism plays no role in Crohn’s disease in Ashkenazi Jews. (PMID:17385031)
• human natural resistance-associated macrophage protein 1 gene might be involved in susceptibility to pulmonary Mycobacterium avium complex infection (PMID:17459898)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Slc11a1	ENSMUSG00000026177
rattus_norvegicus	Slc11a1	ENSRNOG00000014956
drosophila_melanogaster	Mvl	FBGN0011672
caenorhabditis_elegans		WBGENE00004876

Paralogs (1): SLC11A2 (ENSG00000110911)

Protein

Protein identifiers

Natural resistance-associated macrophage protein 1 — P49279 (reviewed: P49279)

Alternative names: Solute carrier family 11 member 1

All UniProt accessions (5): P49279, A0A087X181, A0A087X2D6, A0A0A0MTL3, Q9HBK0

UniProt curated annotations — full annotation on UniProt →

Function. Macrophage-specific antiporter that fluxes metal ions in either direction against a proton gradient. Localized to late endosomal lysosomal membranes, delivers bivalent cations from the cytosol into these acidic compartments where they may directly affect antimicrobial activity. Involved in iron metabolism and host natural resistance to infection with intracellular parasites. Pathogen resistance involves sequestration of Fe(2+) and Mn(2+), cofactors of both prokaryotic and eukaryotic catalases and superoxide dismutases, not only to protect the macrophage against its own generation of reactive oxygen species, but to deny the cations to the pathogen for synthesis of its protective enzymes.

Subcellular location. Late endosome membrane. Lysosome membrane.

Tissue specificity. Macrophages; peripheral blood leukocytes, lung, spleen and liver.

Induction. In response to lymphokine or bacterial products.

Polymorphism. Genetic variation in SLC11A1 is associated with susceptibility to infection with Mycobacterium ulcerans [MIM:610446]. Genetic variations in SLC11A1 determine Mycobacterium tuberculosis susceptibility [MIM:607948].

Similarity. Belongs to the NRAMP family.

Isoforms (2)

UniProt ID	Names	Canonical?
P49279-1	1	yes
P49279-2	2

RefSeq proteins (1): NP_000569* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001046	NRAMP_fam	Family

Pfam: PF01566

Catalyzed reactions (Rhea), 3 shown:

• Zn(2+)(in) + H(+)(out) = Zn(2+)(out) + H(+)(in) (RHEA:28839)
• Fe(2+)(in) + H(+)(out) = Fe(2+)(out) + H(+)(in) (RHEA:29439)
• Mn(2+)(in) + H(+)(out) = Mn(2+)(out) + H(+)(in) (RHEA:73063)

UniProt features (45 total): topological domain 13, transmembrane region 12, sequence conflict 10, sequence variant 3, glycosylation site 2, splice variant 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9F6P	ELECTRON MICROSCOPY	3.7
9F6Q	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49279-F1	83.31	0.44

Functional residue map

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

Glycosylation sites (2): 324, 338

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1222556	ROS and RNS production in phagocytes
R-HSA-425410	Metal ion SLC transporters
R-HSA-6798695	Neutrophil degranulation
R-HSA-6803544	Ion influx/efflux at host-pathogen interface

MSigDB gene sets: 442 (showing top): AP1_01, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, MODULE_45, GOBP_CELLULAR_RESPONSE_TO_CADMIUM_ION

GO Biological Process (42): negative regulation of cytokine production (GO:0001818), positive regulation of cytokine production (GO:0001819), T cell proliferation involved in immune response (GO:0002309), positive regulation of dendritic cell antigen processing and presentation (GO:0002606), positive regulation of T-helper 1 type immune response (GO:0002827), iron ion transport (GO:0006826), manganese ion transport (GO:0006828), intracellular iron ion homeostasis (GO:0006879), phagocytosis (GO:0006909), inflammatory response (GO:0006954), vacuolar acidification (GO:0007035), response to bacterium (GO:0009617), positive regulation of gene expression (GO:0010628), nitrite transport (GO:0015707), antimicrobial humoral response (GO:0019730), metal ion transport (GO:0030001), intracellular manganese ion homeostasis (GO:0030026), response to lipopolysaccharide (GO:0032496), positive regulation of type II interferon production (GO:0032729), response to type II interferon (GO:0034341), iron ion transmembrane transport (GO:0034755), wound healing (GO:0042060), macrophage activation (GO:0042116), defense response to bacterium (GO:0042742), defense response to protozoan (GO:0042832), MHC class II biosynthetic process (GO:0045342), cell redox homeostasis (GO:0045454), respiratory burst (GO:0045730), positive regulation of transcription by RNA polymerase II (GO:0045944), antigen processing and presentation of peptide antigen (GO:0048002), mRNA stabilization (GO:0048255), positive regulation of phagocytosis (GO:0050766), defense response to Gram-negative bacterium (GO:0050829), establishment of localization in cell (GO:0051649), multicellular organismal-level iron ion homeostasis (GO:0060586), cadmium ion transmembrane transport (GO:0070574), cellular detoxification of cadmium ion (GO:0098849), L-arginine transmembrane transport (GO:1903826), monoatomic ion transport (GO:0006811), immune response (GO:0006955)

GO Molecular Function (6): iron ion transmembrane transporter activity (GO:0005381), manganese ion transmembrane transporter activity (GO:0005384), protein homodimerization activity (GO:0042803), transition metal ion transmembrane transporter activity (GO:0046915), metal cation:proton antiporter activity (GO:0051139), metal ion transmembrane transporter activity (GO:0046873)

GO Cellular Component (11): lysosome (GO:0005764), lysosomal membrane (GO:0005765), late endosome (GO:0005770), plasma membrane (GO:0005886), endosome membrane (GO:0010008), phagocytic vesicle membrane (GO:0030670), late endosome membrane (GO:0031902), tertiary granule membrane (GO:0070821), ficolin-1-rich granule membrane (GO:0101003), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Innate Immune System	2
SLC-mediated transmembrane transport	1
Antimicrobial peptides	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transition metal ion transport	3
cytokine production	2
regulation of cytokine production	2
intracellular monoatomic cation homeostasis	2
transition metal ion transmembrane transporter activity	2
endosome	2
secretory granule membrane	2
tertiary granule	2
negative regulation of gene expression	1
negative regulation of multicellular organismal process	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
T cell activation involved in immune response	1
immune response	1
T cell proliferation	1
dendritic cell antigen processing and presentation	1
positive regulation of antigen processing and presentation	1
regulation of dendritic cell antigen processing and presentation	1
positive regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of T-helper 1 type immune response	1
T-helper 1 type immune response	1
inorganic ion homeostasis	1
endocytosis	1
defense response	1
intracellular pH reduction	1
response to other organism	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
inorganic anion transport	1
nitrogen compound transport	1
humoral immune response	1
defense response to symbiont	1
monoatomic cation transport	1
manganese ion homeostasis	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
positive regulation of cytokine production	1
type II interferon production	1

Protein interactions and networks

STRING

2384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC11A1	HAMP	P81172	699
SLC11A1	SLC40A1	Q9NP59	676
SLC11A1	IRGM	A1A4Y4	675
SLC11A1	VIL1	P09327	670
SLC11A1	NOS2	P35228	652
SLC11A1	IFNG	P01579	645
SLC11A1	LTF	P02788	628
SLC11A1	SP110	Q9HB58	627
SLC11A1	NOD2	Q9HC29	618
SLC11A1	CTDSP1	Q9GZU7	615
SLC11A1	TLR2	O60603	610
SLC11A1	IFNGR1	P15260	596
SLC11A1	IL12RB1	P42701	595
SLC11A1	SLC34A1	Q06495	585
SLC11A1	TNP1	P09430	567

IntAct

2 interactions, top by confidence:

A	B	Type	Score
SLC11A1	TRAFD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (32): ABCA3 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), CDS2 (Affinity Capture-MS), CHAMP1 (Affinity Capture-MS), CLGN (Affinity Capture-MS), CUL5 (Affinity Capture-MS), DCAF11 (Affinity Capture-MS), GJA1 (Affinity Capture-MS), HOXC4 (Affinity Capture-MS), LUC7L2 (Affinity Capture-MS), NR1H2 (Affinity Capture-MS), PKP2 (Affinity Capture-MS), PLAGL2 (Affinity Capture-MS), POGZ (Affinity Capture-MS), PSMD4 (Affinity Capture-MS)

ESM2 similar proteins: A0A2K1ZPK4, A0A2K2AIF4, A0A2K2BF92, B9GNS0, B9H7I1, E7EXX2, O22881, O54902, O77741, P41251, P49279, P49280, P49281, P49282, P49283, P51027, P56436, P70553, Q0D7E4, Q21433, Q21434, Q27946, Q27981, Q4R335, Q5QN13, Q5ZHX6, Q6DFC0, Q6DIV6, Q6PF45, Q6YWQ4, Q6ZG85, Q7XIV8, Q869V1, Q8BGY9, Q8BYR8, Q8H3P9, Q8H4H5, Q8UWF0, Q8VDT1, Q8VXB5

Diamond homologs: A0A2K1ZPK4, A0A2K2AIF4, A0A2K2BF92, A0AIM7, A0KG66, A1JLC3, A4TMF6, A4WD10, A5IRZ2, A6QFW1, A6U0S3, A7FGC8, A7X111, B1JFZ6, B2K911, B3W6P3, B5XVU3, B8DE85, B9GNS0, B9H7I1, B9N9Y7, B9NAE4, C1L2Y0, C6D9J9, O54902, O77741, P41251, P49279, P49280, P49281, P49282, P49283, P51027, P56436, P65544, P65545, P70553, P96593, Q03D26, Q03DK0

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
SLC11A1	up-regulates	M1_polarization
IFNG	up-regulates	SLC11A1
PAMPs	up-regulates	SLC11A1
SRC	“up-regulates activity”	SLC11A1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	94
Likely benign	18
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

2892 predictions. Top by Δscore:

Variant	Effect	Δscore
2:218384366:G:GG	donor_gain	1.0000
2:218384370:C:CG	donor_gain	1.0000
2:218384378:GGACC:G	donor_gain	1.0000
2:218384379:GACC:G	donor_gain	1.0000
2:218384406:G:T	donor_gain	1.0000
2:218384417:GC:G	donor_gain	1.0000
2:218384418:C:G	donor_gain	1.0000
2:218385141:TCACA:T	acceptor_loss	1.0000
2:218385142:CACAG:C	acceptor_loss	1.0000
2:218385143:ACAGC:A	acceptor_loss	1.0000
2:218385144:C:G	acceptor_gain	1.0000
2:218385144:CAGCT:C	acceptor_loss	1.0000
2:218385145:A:AG	acceptor_gain	1.0000
2:218385145:AGCT:A	acceptor_loss	1.0000
2:218385146:G:A	acceptor_loss	1.0000
2:218385146:G:GC	acceptor_gain	1.0000
2:218385146:GC:G	acceptor_gain	1.0000
2:218385146:GCTT:G	acceptor_gain	1.0000
2:218385265:AGG:A	donor_loss	1.0000
2:218386695:G:GT	donor_gain	1.0000
2:218386738:G:GT	donor_gain	1.0000
2:218386753:GT:G	donor_gain	1.0000
2:218387158:A:AG	acceptor_gain	1.0000
2:218387159:G:GG	acceptor_gain	1.0000
2:218387159:GA:G	acceptor_gain	1.0000
2:218387231:G:GC	donor_loss	1.0000
2:218387231:G:GG	donor_gain	1.0000
2:218387232:T:G	donor_loss	1.0000
2:218387543:GTTT:G	acceptor_gain	1.0000
2:218387795:TGCA:T	acceptor_loss	1.0000

AlphaMissense

3546 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:218384297:A:C	S69R	0.999
2:218384299:C:A	S69R	0.999
2:218384299:C:G	S69R	0.999
2:218384323:C:A	N77K	0.999
2:218384323:C:G	N77K	0.999
2:218387928:C:A	N256K	0.999
2:218387928:C:G	N256K	0.999
2:218387936:T:C	L259P	0.999
2:218391445:G:T	G372W	0.999
2:218391451:A:C	S374R	0.999
2:218391453:C:A	S374R	0.999
2:218391453:C:G	S374R	0.999
2:218384292:T:A	L67H	0.998
2:218384304:C:A	A71D	0.998
2:218384313:A:G	D74G	0.998
2:218384313:A:T	D74V	0.998
2:218384337:T:C	L82P	0.998
2:218387921:C:A	P254H	0.998
2:218391421:T:A	W364R	0.998
2:218391421:T:C	W364R	0.998
2:218391443:C:A	A371D	0.998
2:218391455:C:A	S375Y	0.998
2:218391455:C:T	S375F	0.998
2:218391475:G:C	A382P	0.998
2:218391478:G:A	G383R	0.998
2:218391478:G:C	G383R	0.998
2:218391479:G:A	G383E	0.998
2:218393122:A:C	S436R	0.998
2:218393124:C:A	S436R	0.998
2:218393124:C:G	S436R	0.998

dbSNP variants (sampled 300 via entrez): RS1000189829 (2:218390065 C>A,G,T), RS1000204732 (2:218390444 T>A), RS1000331553 (2:218395095 G>A,C), RS1000448969 (2:218388048 T>C), RS1000480197 (2:218395644 G>A), RS1000529077 (2:218391459 C>T), RS1000538825 (2:218391627 T>C,G), RS1000724276 (2:218396262 G>A), RS1001071596 (2:218396158 G>C,T), RS1001273852 (2:218383671 G>C), RS1001370916 (2:218380621 C>G), RS1001478016 (2:218385756 G>A), RS1001481615 (2:218389246 G>A), RS1002204767 (2:218392544 C>T), RS1002308142 (2:218384654 G>A)

Disease associations

OMIM: gene MIM:600266 | disease phenotypes: MIM:219700, MIM:610446

GenCC curated gene-disease

Disease	Classification	Inheritance
cystic fibrosis	Supportive	Autosomal recessive
Mycobacterium tuberculosis, susceptibility	Limited	Autosomal dominant

Mondo (3): cystic fibrosis (MONDO:0009061), Buruli ulcer, susceptibility to (MONDO:0012499), Mycobacterium tuberculosis, susceptibility (MONDO:0000070)

Orphanet (1): Cystic fibrosis (Orphanet:586)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000246	Sinusitis
HP:0000365	Hearing impairment
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000787	Nephrolithiasis
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001392	Abnormality of the liver
HP:0001394	Cirrhosis
HP:0001508	Failure to thrive
HP:0001738	Exocrine pancreatic insufficiency
HP:0002020	Gastroesophageal reflux
HP:0002024	Malabsorption
HP:0002035	Rectal prolapse
HP:0002099	Asthma
HP:0002105	Hemoptysis
HP:0002107	Pneumothorax
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002570	Steatorrhea
HP:0002724	Recurrent Aspergillus infections
HP:0002726	Recurrent Staphylococcus aureus infections
HP:0002783	Recurrent lower respiratory tract infections
HP:0002842	Recurrent Burkholderia cepacia infections
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003251	Male infertility
HP:0004401	Meconium ileus
HP:0005376	Recurrent Haemophilus influenzae infections
HP:0006536	Airway obstruction
HP:0012236	Elevated sweat chloride

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000964_14	Ulcerative colitis	1.000000e-10
GCST001725_74	Inflammatory bowel disease	4.000000e-12

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003550	Cystic Fibrosis	C06.689.202; C08.381.187; C16.320.190; C16.614.213
C536092	Mycobacterium tuberculosis, susceptibility to infection by (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2052040 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC11 family of proton-coupled metal ion transporters

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
perfluorooctanoic acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
yessotoxin	increases expression	1
bisphenol S	increases methylation	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Estradiol	decreases expression	1
Mercury	increases expression	1
Methotrexate	decreases expression	1
Ozone	affects expression, increases abundance	1
Smoke	decreases expression	1
Triclosan	decreases expression	1
Cyclosporine	increases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2061615	Binding	Inhibition of NRAMP1 expressed in CHO cells	Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00157690	PHASE4	COMPLETED	Study of Alendronate to Prevent and Treat Osteoporosis in Cystic Fibrosis Patients
NCT00208078	PHASE4	TERMINATED	Effect of Non-Invasive Ventilation in Cystic Fibrosis Patient With Chronic Respiratory Failure.
NCT00244270	PHASE4	COMPLETED	Cystic Fibrosis and Totally Implantable Vascular Access Devices
NCT00333385	PHASE4	TERMINATED	Continuous Versus Short Infusions of Ceftazidime in Cystic Fibrosis
NCT00411736	PHASE4	COMPLETED	Scandinavian Cystic Fibrosis Azithromycin Study
NCT00418470	PHASE4	TERMINATED	Prolonging the Duration of Peripheral Venous Catheters in Cystic Fibrosis People
NCT00431964	PHASE4	COMPLETED	Effect of Azithromycin on Lung Function in 6-18 Year-olds With Cystic Fibrosis (CF) Not Infected With P. Aeruginosa
NCT00434278	PHASE4	TERMINATED	A Trial of Pulmozyme Withdrawal on Exercise Tolerance in Cystic Fibrosis Subjects With Severe Lung Disease (TOPIC)
NCT00483769	PHASE4	COMPLETED	One Year Glargine Treatment in CFRD Children and Adolescents
NCT00528190	PHASE4	COMPLETED	Treatment of Aspergillus Fumigatus (a Fungal Infection) in Patients With Cystic Fibrosis
NCT00557089	PHASE4	COMPLETED	The Effect of rhDNase on Ventilation Inhomogeneity in Patients With Cystic Fibrosis
NCT00572975	PHASE4	COMPLETED	Malabsorption Blood Test:Toward a Novel Approach to Quantify Steatorrhea
NCT00680316	PHASE4	TERMINATED	A Study of Pulmozyme® (Dornase Alpha) in 3- to 5-Year-Old Patients With Cystic Fibrosis
NCT00685035	PHASE4	COMPLETED	Comparison of Airway Clearance Therapy in Cystic Fibrosis Using the Same VEST Therapy Device But With Different Settings
NCT00744250	PHASE4	TERMINATED	Intraduodenal Aspiration Study to Assess the Bioavailability of Oral Pancrecarb® Compared to Placebo Control
NCT00787917	PHASE4	TERMINATED	An Exploratory Study to Assess Multiple Doses of Omalizumab in Patients With Cystic Fibrosis Complicated by Acute Bronchopulmonary Aspergillosis (ABPA)
NCT00843817	PHASE4	COMPLETED	RhDNase and Biodistribution of PMN Serine Proteases in Cystic Fibrosis Sputum
NCT00890370	PHASE4	COMPLETED	Should Any One Airway Clearance Technique be Recommended for People With Cystic Fibrosis?
NCT00996424	PHASE4	TERMINATED	The Effect of Inhaled N-Acetylcysteine Compared to Normal Saline on Sputum Rheology and Lung Function
NCT01044719	PHASE4	UNKNOWN	Duration of Antibiotics in Infective Exacerbations of Cystic Fibrosis
NCT01100606	PHASE4	COMPLETED	A Study to Evaluate the Mode of Administration and Safety of EUR-1008 (APT-1008) in Infants 1 to 12 Months of Age
NCT01131507	PHASE4	COMPLETED	PR-018: An Open-Label, Safety Extension of Study PR-011
NCT01207245	PHASE4	COMPLETED	Circadian Rhythm In Tobramycin Elimination In Cystic Fibrosis
NCT01323101	PHASE4	COMPLETED	Doxycycline Effects on Inflammation in Cystic Fibrosis
NCT01327703	PHASE4	COMPLETED	Control of Steatorrhea in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency
NCT01377792	PHASE4	COMPLETED	Study of Long-term Treatment With Hypertonic Saline in Patients With Cystic Fibrosis
NCT01400750	PHASE4	COMPLETED	Comparison of 2 Treatment Regimens for Eradication of P Aeruginosa Infection in Children With Cystic Fibrosis
NCT01429259	PHASE4	COMPLETED	Population Pharmacokinetics of Prolonged Infusion Meropenem in Cystic Fibrosis (CF) Children
NCT01608555	PHASE4	COMPLETED	Tobramycin 300 mg Once-a-day (o.d.) Aerosol in Adults With Cystic Fibrosis
NCT01667094	PHASE4	UNKNOWN	A Study Comparing Continuous Infusion Antibiotics to Standard Treatment for Lung Infections in Cystic Fibrosis
NCT01694069	PHASE4	TERMINATED	Continuous Infusion Piperacillin-tazobactam for the Treatment of Cystic Fibrosis
NCT01702415	PHASE4	WITHDRAWN	Zoledronic Acid in Cystic Fibrosis
NCT01712334	PHASE4	COMPLETED	A Study of the Comparable Efficacy and Safety of Pulmozyme (Dornase Alfa) Delivered by the eRapid Nebulizer System in Patients With Cystic Fibrosis
NCT01737983	PHASE4	COMPLETED	Effect of Lactobacillus Reuteri in Cystic Fibrosis
NCT01844778	PHASE4	COMPLETED	Ease of Use and Microbial Contamination of Tobramycin Inhalation Powder (TIP) Versus Nebulised Tobramycin Inhalation Solution (TIS) and Nebulised Colistimethate (COLI)
NCT01880346	PHASE4	COMPLETED	Comparison of Absorption of Vitamin D in Cystic Fibrosis
NCT01882400	PHASE4	COMPLETED	Assessment of Response to Treatment of Osteoporosis With Oral Bisphosphonates in Patients With Muscular Dystrophy
NCT01937325	PHASE4	UNKNOWN	CPET in CF Patients With One G551D Mutation Taking VX770
NCT02015663	PHASE4	TERMINATED	Tobramycin Inhalation Powder (TIP) Administered Once Daily Continuously Versus TIP Administered BID in 28 Day on / 28 Day Off Cycles
NCT02048592	PHASE4	UNKNOWN	Impact of Immunonutrition on the Patients With Cystic Fibrosis