FTL

Summary

FTL (ferritin light chain, HGNC:3999) is a protein-coding gene on chromosome 19q13.33, encoding Ferritin light chain (P02792). Stores iron in a soluble, non-toxic, readily available form.

This gene encodes the light subunit of the ferritin protein. Ferritin is the major intracellular iron storage protein in prokaryotes and eukaryotes. It is composed of 24 subunits of the heavy and light ferritin chains. Variation in ferritin subunit composition may affect the rates of iron uptake and release in different tissues. A major function of ferritin is the storage of iron in a soluble and nontoxic state. Defects in this light chain ferritin gene are associated with several neurodegenerative diseases and hyperferritinemia-cataract syndrome. This gene has multiple pseudogenes.

Source: NCBI Gene 2512 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary hyperferritinemia with congenital cataracts (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 238 total — 19 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 80
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000146

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3999
Approved symbol	FTL
Name	ferritin light chain
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	MGC71996, NBIA3, FTL1
Ensembl gene	ENSG00000087086
Ensembl biotype	protein_coding
OMIM	134790
Entrez	2512

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000331825, ENST00000718269, ENST00000853538, ENST00000853539, ENST00000853540, ENST00000853541, ENST00000853542, ENST00000853543, ENST00000925220, ENST00000925221, ENST00000925222

RefSeq mRNA: 1 — MANE Select: NM_000146 NM_000146

CCDS: CCDS33070

Canonical transcript exons

ENST00000331825 — 4 exons

Exon	Start	End
ENSE00000718697	48965770	48965916
ENSE00000718702	48966281	48966406
ENSE00001226683	48965309	48965609
ENSE00001316584	48966583	48966879

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4264.3154 / max 99303.4495, expressed in 1828 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176894	4234.5267	1828
176895	16.6895	1707
176902	8.2584	1409
176903	1.6515	674
176897	1.2432	725
176898	0.6185	291
176899	0.4579	196
176896	0.4507	207
176900	0.3017	119
176901	0.1174	57

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.98	gold quality
blood	UBERON:0000178	99.97	gold quality
gall bladder	UBERON:0002110	99.97	gold quality
upper lobe of left lung	UBERON:0008952	99.97	gold quality
monocyte	CL:0000576	99.96	gold quality
leukocyte	CL:0000738	99.96	gold quality
islet of Langerhans	UBERON:0000006	99.96	gold quality
adipose tissue	UBERON:0001013	99.96	gold quality
spleen	UBERON:0002106	99.96	gold quality
right lung	UBERON:0002167	99.96	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.96	gold quality
ascending aorta	UBERON:0001496	99.95	gold quality
thoracic aorta	UBERON:0001515	99.95	gold quality
right coronary artery	UBERON:0001625	99.95	gold quality
left coronary artery	UBERON:0001626	99.95	gold quality
descending thoracic aorta	UBERON:0002345	99.95	gold quality
omental fat pad	UBERON:0010414	99.95	gold quality
granulocyte	CL:0000094	99.94	gold quality
adult mammalian kidney	UBERON:0000082	99.94	gold quality
right lobe of liver	UBERON:0001114	99.94	gold quality
right lobe of thyroid gland	UBERON:0001119	99.94	gold quality
left lobe of thyroid gland	UBERON:0001120	99.94	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.94	gold quality
temporal lobe	UBERON:0001871	99.93	gold quality
caudate nucleus	UBERON:0001873	99.93	gold quality
putamen	UBERON:0001874	99.93	gold quality
amygdala	UBERON:0001876	99.93	gold quality
nucleus accumbens	UBERON:0001882	99.93	gold quality
placenta	UBERON:0001987	99.93	gold quality
substantia nigra	UBERON:0002038	99.93	gold quality

Single-cell (SCXA)

Detected in 91 experiment(s), a significant marker in 71.

Experiment	Marker?	Max mean expression
E-MTAB-8207	yes	151987.32
E-MTAB-10553	yes	137640.12
E-MTAB-6653	yes	129144.87
E-MTAB-7407	yes	128143.59
E-CURD-98	yes	120119.29
E-HCAD-9	yes	108996.84
E-MTAB-8495	yes	101624.48
E-MTAB-9435	yes	95959.09
E-MTAB-8322	yes	95434.79
E-MTAB-6701	yes	86030.60
E-CURD-122	yes	81587.98
E-HCAD-15	yes	80532.37
E-MTAB-6308	yes	78670.81
E-GEOD-84465	yes	69042.63
E-CURD-126	yes	68548.85

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFE2L2

miRNA regulators (miRDB)

9 targeting FTL, 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-22-3P	99.93	68.13	917
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-6882-3P	98.23	67.01	1119
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-1258	96.08	67.74	700

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• gene coding and flanking regions were sequenced and examined for mutations that might modulate the iron burden of individuals harboring the common mutant hemochromatosis HFE genotype or cause hemochromatosis independent of mutations in the HFE gene (PMID:11783942)
• Analysis of sequence effect on folding efficiency of ferritin heavy and light subunits. (PMID:12387819)
• The genetic defects in the FTL gene are unlikely to be a common cause of typical PD, at least in a North America population. (PMID:12459518)
• autosomal dominant basal ganglia disorder caused by an adenine insertion at position 460-461 of the gene for ferritin light polypeptide (FTL) in a French family (PMID:12746423)
• Adult-onset generalized dystonia due to a mutation in ferritin, light polypeptide. (PMID:15390032)
• Intra-leukocytic hemosiderin inclusions (a complex of ferritin, denatured ferritin and other material) are associated with iron overload and acute infection. (PMID:15727900)
• Results describe an hereditary ferritinopathy with a novel mutation (C insertion at nt646-647 in exon 4) in the ferritin light chain gene, resulting in a longer than normal protein. (PMID:15835264)
• Results describe the combined effects of DNA transcription and mRNA translation regulation of ferritin-L synthesis. (PMID:16217041)
• Quantitative RNA analysis confirmed down-regulation of ferritin light polypeptide and insulin-like growth factor binding protein 1 in hydatiform mole increased incidence of gestational trophoblastic neoplasia. (PMID:16222695)
• These results demonstrate that, in a human metastatic melanoma cell line, the stress condition promoted by L-ferritin down-modulation, can substantially influence proper maturation of tyrosinase (PMID:16252260)
• X-ray structures of recombinant human L-chain ferritin (HuLF) show a cluster of acidic residues at the ferrihydrite nucleation site and at the iron channel along the threefold axis, and an ordered Cd2+ structure within the iron channel. (PMID:16790936)
• The findings suggest that the pathogenic effects of Ln1 expression are more likely due to deregulation of cellular iron homeostasis rather than to protein conformational problems. (PMID:16822677)
• Demonstrated iron uptake by ferritins into multiple organs. Uptake is greater when iron delivered by H-ferritin compared to L-ferritin. (PMID:17459943)
• FTL is a marker gene useful for stratifying osteosarcoma patients into low- and high-risk groups and predicting therapy outcome. (PMID:17660802)
• We have detected a significant inverse correlation of -0.565 (P<0.0001) between serum ferritin when <50 microg/L and FGF-23. (PMID:17761032)
• metacarpophalangeal arthropathy was independently associated with older age, higher ferritin, the presence of the C282Y +/+ and C282Y/H63D hemochromatosis protein(HFE) genotypes and higher percentage of transferrin saturation. (PMID:18061976)
• FTL and FTH subunits respond independently to cellular iron concentrations (PMID:18160403)
• In exon 4 of the FTL gene, duplication of the 469-484 sequence is found replacing the C-terminal 14 amino acid residues with a novel 23 amino acid sequence. (PMID:18413574)
• placental Ferritin protein expression decreased slightly in mild anemia but significantly in moderate anemia (PMID:18586377)
• the rate of change of serum ferritin in untreated HFE (hemochromatosis protein) C282Y homozygotes is highly variable and may increase or decrease over time (PMID:18665827)
• hereditary ferritinopathy pathogenesis is likely to result from a combination of reduction in iron storage function (PMID:18755684)
• The missense mutation of FTL represents a new cause of genetic hyperferritinemia without iron overload, and the mutation may increase the efficacy of L ferritin secretion by increasing the hydrophobicity of the N terminal “A” alpha helix. (PMID:19176363)
• Study hypothesize that changes in the expression of the L ferritin might be linked, at least to a certain extent, to the pathogenesis of this rare eye disease. (PMID:19254706)
• Finding not only supports direct evidence for a regulatory role of L-ferritin in neuroectodermal cell pigmentation but also integrates a new player within a complicated network governing iron homeostasis in the dopamine neurons of substantia nigra. (PMID:19318681)
• gene expression analysis of iron management proteins in the liver of trangenic mice indicates that the FTL transgenic mouse liver is iron deficient (PMID:19519778)
• indicate that cellular iron imbalance and oxidative damage produced by the over-expression in of two pathogenic L-ferritin variants are primary causes of cell death, while aggregate formation is a secondary effect (PMID:19781644)
• identified mutations in HFE, SLC40A1, HAMP, HJV, TFR2, and FTL that could explain TRANSFERRIN SATURATION/SERUM FERRITIN heterogeneity in adults with previous HFE genotyping to detect C282Y and H63D; results were correlated with racial groups (PMID:19787796)
• the x-ray crystallographic structure and report functional studies of ferritin homopolymers formed from the mutant FTL polypeptide (PMID:19923220)
• Expression of FTL and FTH genes encoding ferretin subunits in lung and renal carcinomas (PMID:20088381)
• biochemical and crystallographic characterization of pathogenic FTL mutant p.Phe167SerfsX26 showing that it is a functional ferritin with an altered conformation of the C terminus (PMID:20159981)
• Toluene diisocyanate (TDI) regulates haem oxygenase-1/ferritin expression: implications for toluene diisocyanate-induced asthma. (PMID:20345975)
• This protein has been found differentially expressed in the anterior cingulate cortex from patients with schizophrenia (PMID:20381070)
• This protein has been found differentially expressed in thalami from patients with schizophrenia. (PMID:20471030)
• The study shows the facile assembly of mutant FTL and FTH1 subunits into soluble ferritin heteropolymers, but their ability to incorporate iron was significantly reduced relative to wild-type-FTL/FTH1 heteropolymers. (PMID:21029774)
• Somatic mutations in the iron response elements (IRE) of the L-ferritin gene are infrequent in the age-related cataract. (PMID:21139976)
• In the family with hyperferritinemia cataract syndrome a G–>C heterozygous mutation at position +32 of FTL was identified. (PMID:21541272)
• FTL is a target gene of the BACH1 transcription factor according to ChIP-seq analysis in HEK 293 cells. (PMID:21555518)
• genetic variations in the HFE gene, but not plasma ferritin may have a role in coronary heart disease in Chinese (PMID:21696736)
• Genetic analysis revealed mutation G32A in Pedigree 1 and mutation G32T in Pedigree 2, both heterozygous and located in the iron-responsive element of the ferritin light chain mRNA in hyperferritinemia cataract syndrome. (PMID:21907119)
• Molecular genetic analysis revealed point mutations within the FTL IRE. (PMID:22020773)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:56095	ENSDARG00000018461
danio_rerio	zgc:172145	ENSDARG00000045586
mus_musculus	Ftl1	ENSMUSG00000050708
mus_musculus	Ftl1-ps1	ENSMUSG00000062382
rattus_norvegicus	AC115277.1	ENSRNOG00000004662
rattus_norvegicus	Ftl1l7	ENSRNOG00000029082
rattus_norvegicus	LOC120102993	ENSRNOG00000031506
rattus_norvegicus	LOC100362384	ENSRNOG00000031540
rattus_norvegicus	Ftl1l2	ENSRNOG00000033776
rattus_norvegicus	AABR07041778.1	ENSRNOG00000034150
rattus_norvegicus	Ftl1	ENSRNOG00000064385
rattus_norvegicus	LOC100360087	ENSRNOG00000064482
rattus_norvegicus	Ftl1-ps14	ENSRNOG00000065602
drosophila_melanogaster	Fer3HCH	FBGN0030449
caenorhabditis_elegans		WBGENE00001500
caenorhabditis_elegans	ftn-2	WBGENE00001501

Paralogs (3): FTHL17 (ENSG00000132446), FTH1 (ENSG00000167996), FTMT (ENSG00000181867)

Protein

Protein identifiers

Ferritin light chain — P02792 (reviewed: P02792)

All UniProt accessions (2): P02792, A0A384MDR3

UniProt curated annotations — full annotation on UniProt →

Function. Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation. Also plays a role in delivery of iron to cells. Mediates iron uptake in capsule cells of the developing kidney. Delivery to lysosomes by the cargo receptor NCOA4 for autophagic degradation and release or iron.

Subunit / interactions. Oligomer of 24 subunits. There are two types of subunits: L (light) chain and H (heavy) chain. The major chain can be light or heavy, depending on the species and tissue type. The functional molecule forms a roughly spherical shell with a diameter of 12 nm and contains a central cavity into which the insoluble mineral iron core is deposited. Iron enters the spherical protein shell through pores that are formed between subunits. Mutations leading to truncation or the addition of extra residues at the C-terminus interfere with normal pore formation and with iron accumulation. Interacts with NCOA4.

Subcellular location. Cytoplasmic vesicle. Autophagosome. Cytoplasm. Autolysosome.

Disease relevance. Hyperferritinemia with or without cataract (HRFTC) [MIM:600886] An autosomal dominant disease characterized by elevated level of ferritin in serum and tissues, and early-onset bilateral cataract. Cataracts may be subclinical in some patients. The disease is caused by variants affecting the gene represented in this entry. Neurodegeneration with brain iron accumulation 3 (NBIA3) [MIM:606159] A neurodegenerative disorder associated with iron accumulation in the brain, primarily in the basal ganglia. It is characterized by a variety of neurological signs including parkinsonism, ataxia, corticospinal signs, mild non-progressive cognitive deficit and episodic psychosis. It is linked with decreased serum ferritin levels. The disease is caused by variants affecting the gene represented in this entry. L-ferritin deficiency (LFTD) [MIM:615604] A condition characterized by low levels of ferritin in serum and tissues in the absence of other hematological symptoms. Seizures and mild neuropsychologic impairment may manifest in individuals with complete ferritin deficiency. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ferritin family.

RefSeq proteins (1): NP_000137* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001519	Ferritin	Family
IPR008331	Ferritin_DPS_dom	Domain
IPR009040	Ferritin-like_diiron	Domain
IPR009078	Ferritin-like_SF	Homologous_superfamily
IPR012347	Ferritin-like	Homologous_superfamily
IPR014034	Ferritin_CS	Conserved_site

Pfam: PF00210

UniProt features (27 total): helix 7, sequence conflict 6, binding site 5, sequence variant 2, turn 2, initiator methionine 1, chain 1, domain 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
3KXU	X-RAY DIFFRACTION	1.85
2FFX	X-RAY DIFFRACTION	1.9
5LG8	X-RAY DIFFRACTION	1.98
6WX6	ELECTRON MICROSCOPY	2
6TSF	X-RAY DIFFRACTION	2.09
2FG4	X-RAY DIFFRACTION	2.1
9BPK	ELECTRON MICROSCOPY	2.1
6TSA	X-RAY DIFFRACTION	2.18
6TS0	X-RAY DIFFRACTION	2.2
6TS1	X-RAY DIFFRACTION	2.2
6TSJ	X-RAY DIFFRACTION	2.3
9BQ5	ELECTRON MICROSCOPY	2.36
6TR9	X-RAY DIFFRACTION	2.46
2FG8	X-RAY DIFFRACTION	2.5
9BPJ	ELECTRON MICROSCOPY	2.85
4V6B	X-RAY DIFFRACTION	2.85
9BPI	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02792-F1	96.69	0.96

Functional residue map

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

Ligand- & substrate-binding residues (5): 54; 57; 58; 61; 64

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-3000480	Scavenging by Class A Receptors
R-HSA-432722	Golgi Associated Vesicle Biogenesis
R-HSA-6798695	Neutrophil degranulation
R-HSA-917937	Iron uptake and transport

MSigDB gene sets: 414 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, REACTOME_INNATE_IMMUNE_SYSTEM, HARRIS_HYPOXIA, GOCC_SECRETORY_GRANULE, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, MODULE_128, HSIAO_HOUSEKEEPING_GENES, JOHANSSON_GLIOMAGENESIS_BY_PDGFB_UP, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, REACTOME_MEMBRANE_TRAFFICKING, GOBP_IRON_ION_TRANSPORT

GO Biological Process (2): iron ion transport (GO:0006826), intracellular iron ion homeostasis (GO:0006879)

GO Molecular Function (6): iron ion binding (GO:0005506), ferrous iron binding (GO:0008198), ferric iron binding (GO:0008199), identical protein binding (GO:0042802), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (11): extracellular region (GO:0005576), cytoplasm (GO:0005737), autophagosome (GO:0005776), cytosol (GO:0005829), membrane (GO:0016020), azurophil granule lumen (GO:0035578), autolysosome (GO:0044754), extracellular exosome (GO:0070062), ferritin complex (GO:0070288), lysosome (GO:0005764), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Binding and Uptake of Ligands by Scavenger Receptors	1
trans-Golgi Network Vesicle Budding	1
Innate Immune System	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
iron ion binding	2
cytoplasm	2
transition metal ion transport	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
transition metal ion binding	1
protein binding	1
binding	1
cation binding	1
intracellular anatomical structure	1
vacuole	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1
secondary lysosome	1
extracellular vesicle	1
protein-containing complex	1
lytic vacuole	1
intracellular vesicle	1

Protein interactions and networks

STRING

2198 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FTL	FTH1	P02794	983
FTL	SLC40A1	Q9NP59	929
FTL	PANK2	Q9BZ23	907
FTL	PLA2G6	O60733	907
FTL	SLC11A2	P49281	883
FTL	IREB2	P48200	853
FTL	TFRC	P02786	849
FTL	ACO1	P21399	798
FTL	HAMP	P81172	785
FTL	HFE	Q30201	759
FTL	NCOA4	Q13772	755
FTL	SCARA5	Q6ZMJ2	751
FTL	PANK1	Q8TE04	743
FTL	HMOX1	P09601	731
FTL	PCBP1	Q15365	621

IntAct

184 interactions, top by confidence:

A	B	Type	Score
FTL	FTL	psi-mi:“MI:0915”(physical association)	0.940
FTL	FTH1	psi-mi:“MI:0915”(physical association)	0.940
FTH1	FTL	psi-mi:“MI:0915”(physical association)	0.940
FTL	FTL	psi-mi:“MI:0407”(direct interaction)	0.940
FTH1	FTL	psi-mi:“MI:0914”(association)	0.940
NCOA4	FTL	psi-mi:“MI:0914”(association)	0.790
NCOA4	FTL	psi-mi:“MI:0915”(physical association)	0.790

BioGRID (385): FTL (Two-hybrid), FTL (Two-hybrid), KPNA3 (Two-hybrid), MYOG (Two-hybrid), SDCBP (Two-hybrid), USHBP1 (Two-hybrid), FTL (Two-hybrid), FTL (Affinity Capture-MS), FTL (Affinity Capture-MS), FTL (Affinity Capture-MS), FTL (Two-hybrid), FTL (Two-hybrid), FTL (Affinity Capture-Western), FTL (Two-hybrid), FTL (Two-hybrid)

ESM2 similar proteins: O46119, O46414, O46415, P02791, P02792, P02793, P02794, P07229, P07797, P07798, P08267, P09451, P09528, P0A999, P0A9A1, P17663, P18685, P19130, P19132, P19133, P25319, P25320, P25915, P29389, P29391, P42577, P49946, P49947, P49948, P80145, P85835, P85836, P85837, P85838, P85839, Q26061, Q2MHN1, Q2MHN2, Q2YDI9, Q53VB8

Diamond homologs: A0A7E5WTY7, I4DJ24, O46119, O46414, O46415, O65100, P02791, P02792, P02793, P02794, P07229, P07797, P07798, P08267, P09451, P09528, P0C7X4, P17663, P18685, P18686, P19130, P19132, P19133, P19975, P19976, P25319, P25320, P25699, P25915, P29036, P29389, P29390, P29391, P42577, P42578, P49946, P49947, P49948, P80145, P85835

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FTL	“form complex”	Ferritin

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	6
Uncertain significance	142
Likely benign	37
Benign	6

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1298779	NM_000146.4(FTL):c.172G>T (p.Glu58Ter)	Pathogenic
1321316	NM_000146.4(FTL):c.-161C>G	Pathogenic
16474	NM_000146.4(FTL):c.-160A>G	Pathogenic
16475	NM_000146.4(FTL):c.-159G>C	Pathogenic
16478	NM_000146.4(FTL):c.-189_-161del	Pathogenic
16479	NM_000146.4(FTL):c.-168G>T	Pathogenic
16484	NM_000146.4(FTL):c.-175_-170del	Pathogenic
16486	NM_000146.4(FTL):c.286G>A (p.Ala96Thr)	Pathogenic
16487	NM_000146.4(FTL):c.498_499dup (p.Phe167fs)	Pathogenic
16489	NM_000146.4(FTL):c.458dup (p.His153fs)	Pathogenic
1698387	NM_000146.4(FTL):c.460dup (p.Arg154fs)	Pathogenic
2041512	NM_000146.4(FTL):c.460_461delinsCCA (p.Arg154fs)	Pathogenic
2197338	NM_000146.4(FTL):c.-151A>G	Pathogenic
3897670	NM_000146.4(FTL):c.351delinsTTT (p.Gly118fs)	Pathogenic
3897671	NM_000146.4(FTL):c.501dup (p.Glu168fs)	Pathogenic
4537508	NM_000146.4(FTL):c.-164C>G	Pathogenic
647521	NM_000146.4(FTL):c.-157G>A	Pathogenic
963917	NM_000146.4(FTL):c.-167C>T	Pathogenic
96690	NM_000146.4(FTL):c.310G>T (p.Glu104Ter)	Pathogenic
1052512	NM_000146.4(FTL):c.-166T>C	Likely pathogenic
16482	NM_000146.4(FTL):c.-149G>C	Likely pathogenic
16488	NM_000146.4(FTL):c.469_484dup (p.Leu162fs)	Likely pathogenic
2138316	NM_000146.4(FTL):c.-153G>A	Likely pathogenic
450423	NM_000146.4(FTL):c.370_373del (p.Pro124fs)	Likely pathogenic
4845668	NM_000146.4(FTL):c.335del (p.Leu112fs)	Likely pathogenic

SpliceAI

187 predictions. Top by Δscore:

Variant	Effect	Δscore
19:48965606:TCTG:T	donor_gain	1.0000
19:48965606:TCTGG:T	donor_loss	1.0000
19:48965607:CTG:C	donor_gain	1.0000
19:48965607:CTGGT:C	donor_loss	1.0000
19:48965608:TG:T	donor_gain	1.0000
19:48965608:TGGTG:T	donor_loss	1.0000
19:48965609:GG:G	donor_gain	1.0000
19:48965610:G:GG	donor_gain	1.0000
19:48965765:C:A	acceptor_gain	1.0000
19:48965765:CGTA:C	acceptor_loss	1.0000
19:48965766:GTA:G	acceptor_loss	1.0000
19:48965768:A:AG	acceptor_gain	1.0000
19:48965768:AG:A	acceptor_gain	1.0000
19:48965768:AGG:A	acceptor_gain	1.0000
19:48965768:AGGG:A	acceptor_loss	1.0000
19:48965769:G:A	acceptor_gain	1.0000
19:48965769:G:GG	acceptor_gain	1.0000
19:48965769:GGG:G	acceptor_gain	1.0000
19:48965769:GGGC:G	acceptor_gain	1.0000
19:48965769:GGGCT:G	acceptor_gain	1.0000
19:48965914:AAG:A	donor_loss	1.0000
19:48965916:GGT:G	donor_loss	1.0000
19:48965917:GT:G	donor_loss	1.0000
19:48966275:A:AG	acceptor_gain	1.0000
19:48966276:T:G	acceptor_gain	1.0000
19:48966277:A:AG	acceptor_gain	1.0000
19:48966277:ATAG:A	acceptor_loss	1.0000
19:48966278:T:G	acceptor_gain	1.0000
19:48966278:TA:T	acceptor_loss	1.0000
19:48966279:A:AG	acceptor_gain	1.0000

AlphaMissense

1159 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:48965884:C:A	R73S	0.985
19:48965779:T:C	F38L	0.984
19:48965781:C:A	F38L	0.984
19:48965781:C:G	F38L	0.984
19:48966636:G:C	K143N	0.980
19:48966636:G:T	K143N	0.980
19:48966592:T:C	F129L	0.978
19:48966594:C:A	F129L	0.978
19:48966594:C:G	F129L	0.978
19:48966706:T:C	F167L	0.977
19:48966708:C:A	F167L	0.977
19:48966708:C:G	F167L	0.977
19:48965888:G:T	G74V	0.974
19:48965885:G:C	R73P	0.973
19:48966607:T:C	F134L	0.968
19:48966609:C:A	F134L	0.968
19:48966609:C:G	F134L	0.968
19:48965877:A:C	Q70H	0.967
19:48965877:A:T	Q70H	0.967
19:48966398:G:C	D123H	0.967
19:48965888:G:A	G74D	0.966
19:48966372:T:C	L114P	0.966
19:48965887:G:C	G74R	0.964
19:48966383:G:C	G118R	0.963
19:48966643:G:C	G146R	0.963
19:48965786:G:C	R40P	0.960
19:48965818:T:C	F51L	0.957
19:48965820:C:A	F51L	0.957
19:48965820:C:G	F51L	0.957
19:48965561:C:A	N18K	0.956

dbSNP variants (sampled 300 via entrez): RS1001818680 (19:48967194 C>A,T), RS1001849563 (19:48967253 C>T), RS1003834883 (19:48964060 G>T), RS1008098709 (19:48964469 TG>T), RS1008403832 (19:48964891 C>T), RS1008728163 (19:48963692 G>T), RS1011578950 (19:48965210 CG>C), RS1011827651 (19:48964557 C>A,T), RS1011886324 (19:48964041 G>A,C), RS1011963910 (19:48965402 G>T), RS1012254633 (19:48965247 C>G), RS1012266866 (19:48964826 C>G,T), RS1012327406 (19:48963720 GAAAA>G,GA,GAAA,GAAAAA), RS1012743580 (19:48965524 G>A), RS1013107150 (19:48964375 T>C,G)

Disease associations

OMIM: gene MIM:134790 | disease phenotypes: MIM:600886, MIM:606159, MIM:615604, MIM:190300

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary hyperferritinemia with congenital cataracts	Definitive	Autosomal dominant
neuroferritinopathy	Strong	Autosomal dominant
L-ferritin deficiency	Strong	Autosomal dominant
genetic hyperferritinemia without iron overload	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary hyperferritinemia with congenital cataracts	Definitive	AD

Mondo (5): hereditary hyperferritinemia with congenital cataracts (MONDO:0010952), neuroferritinopathy (MONDO:0011638), L-ferritin deficiency (MONDO:0014274), essential tremor (MONDO:0003233), (MONDO:0016788)

Orphanet (4): Neuroferritinopathy (Orphanet:157846), Hereditary hyperferritinemia-cataract syndrome (Orphanet:163), L-ferritin deficiency (Orphanet:440731), NON RARE IN EUROPE: Hereditary essential tremor (Orphanet:862)

HPO phenotypes

80 total (30 of 80 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000338	Hypomimic face
HP:0000518	Cataract
HP:0000643	Blepharospasm
HP:0000709	Psychosis
HP:0000712	Emotional lability
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000734	Disinhibition
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001266	Choreoathetosis
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001596	Alopecia
HP:0001618	Dysphonia
HP:0001621	Weak voice
HP:0001686	Loss of voice
HP:0001808	Fragile nails
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002015	Dysphagia
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002072	Chorea

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D020329	Essential Tremor	C10.228.662.350
C538137	Hyperferritinemia, hereditary, with congenital cataracts (supp.)
C548080	Neuroferritinopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

176 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, decreases reaction, increases expression, decreases expression, affects cotreatment	19
Tobacco Smoke Pollution	affects expression, increases expression, increases methylation	9
methylmercuric chloride	increases expression, affects cotreatment	4
bisphenol A	increases expression, affects expression, decreases expression	4
trichostatin A	increases expression, affects cotreatment	4
Arsenic	affects cotreatment, affects methylation, increases abundance, increases expression	4
Deferoxamine	increases reaction, increases expression, decreases abundance, decreases expression, affects binding (+1 more)	4
Tretinoin	affects cotreatment, increases expression	4
Particulate Matter	increases abundance, increases expression, affects expression	4
lead acetate	increases expression	3
sodium arsenate	increases abundance, increases expression	3
arsenite	increases reaction, increases abundance, increases expression, affects binding	3
cadmium sulfate	increases expression	3
Arsenic Trioxide	increases expression, affects cotreatment	3
Antimony Potassium Tartrate	increases abundance, increases expression, decreases expression, increases reaction, affects reaction (+1 more)	3
Iron	decreases reaction, decreases expression, increases abundance, increases expression, affects binding (+3 more)	3
Valproic Acid	increases expression	3
Vitamin K 3	affects expression, affects binding, increases reaction, increases expression	3
ferric ammonium citrate	increases abundance, increases expression	2
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases expression, increases expression	2
diallyl trisulfide	increases expression, affects reaction, decreases expression, decreases reaction, increases degradation	2
mercuric bromide	increases expression, affects cotreatment	2
ethyl maltol	increases abundance, increases expression, increases response to substance, decreases expression	2
ferrostatin-1	decreases reaction, increases expression, decreases expression, increases abundance	2
Aerosols	affects expression, increases expression	2
Air Pollutants	increases abundance, increases expression	2
Cadmium	affects binding, increases abundance, increases expression	2
Chloroquine	increases abundance, affects expression, affects reaction, affects response to substance, decreases expression (+1 more)	2
Cisplatin	decreases reaction, increases expression, affects reaction, affects cotreatment	2
Copper	increases expression, increases response to substance, affects binding, increases abundance	2

Cellosaurus cell lines

9 cell lines: 9 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1SD	Abcam HeLa FTL KO 1	Cancer cell line	Female
CVCL_B1SE	Abcam HeLa FTL KO 2	Cancer cell line	Female
CVCL_B7XE	Abcam Raji FTL KO	Cancer cell line	Male
CVCL_B9Y3	Abcam THP-1 FTL KO	Cancer cell line	Male
CVCL_C6ZX	Abcam PC-3 FTL KO	Cancer cell line	Male
CVCL_F2A0	mCherry-FTL WT RAW 264.7	Cancer cell line	Male
CVCL_F2A1	mCherry-FTL LRRK2 G2019S RAW 264.7	Cancer cell line	Male
CVCL_SN95	HAP1 FTL (-) 1	Cancer cell line	Male
CVCL_SN96	HAP1 FTL (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00439699	PHASE4	COMPLETED	A Pilot Clinical Trial Of Memantine for Essential Tremor
NCT00584376	PHASE4	COMPLETED	Pregabalin (Lyrica) for the Treatment of Essential Tremor
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02111369	PHASE4	COMPLETED	Propranolol and Botulinum Toxin for Essential Vocal Tremor
NCT02495883	PHASE4	COMPLETED	Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response
NCT00018564	PHASE3	COMPLETED	Novel Therapies for Essential Tremor
NCT00236496	PHASE3	COMPLETED	A Comparison of the Efficacy and Safety of Topiramate Versus Placebo in Treating Tremor of Unknown Cause.
NCT01441284	PHASE3	WITHDRAWN	Efficacy of Pramipexole Extended Release in the Treatment of Essential Tremor
NCT04193527	PHASE3	COMPLETED	A Study to Evaluate the Diagnostic Efficacy of DaTSCAN™ Ioflupane (123I) Injection in Single Photon Emission Computed Tomography (SPECT) for the Diagnosis of Parkinsonian Syndrome (PS) in Chinese Patients
NCT04265209	PHASE3	COMPLETED	[18F] LBT-999 PET Compared to [123I]-FP/CIT SPECT to Distinguish Between Parkinson’s Diseases and Essential Tremor
NCT06087276	PHASE3	ENROLLING_BY_INVITATION	Essential 3 - Decentralized, Phase 3 Study Evaluating the Safety and Efficacy of Ulixacaltamide in Essential Tremor (ET)
NCT00080366	PHASE2	COMPLETED	Octanol to Treat Essential Tremor
NCT00102596	PHASE2	COMPLETED	Clinical Trial Characterizing the Bioavailability of 1-Octanol in Adults With Ethanol-responsive Essential Tremor
NCT00223743	PHASE2	COMPLETED	A Safety/Efficacy Trial of Zonisamide for Essential Tremor
NCT00321087	PHASE2	TERMINATED	A Study of T2000 in Essential Tremor
NCT00598078	PHASE2	COMPLETED	Multiple-dose,Double-blind,Placebo-controlled Study of Sodium Oxybate in Patients With Essential Tremor
NCT00655278	PHASE2	TERMINATED	T2000 in Essential Tremor - Open Label Continuation
NCT01332695	PHASE2	COMPLETED	A Pilot Efficacy and Safety Study of ST101 in Essential Tremor
NCT02277106	PHASE2	COMPLETED	Evaluate SAGE-547 in Participants With Essential Tremor
NCT02551848	PHASE2	UNKNOWN	Kinematic-based BoNT-A Injections for Bilateral ET
NCT02668146	PHASE2	UNKNOWN	An Efficacy/Safety Study of Perampanel for Reducing Essential Tremor
NCT02978781	PHASE2	COMPLETED	A Study to Evaluate SAGE-217 in Participants With Essential Tremor
NCT03101241	PHASE2	COMPLETED	A Phase 2 RCT Study of CX-8998 for Essential Tremor
NCT03688685	PHASE2	COMPLETED	A Clinical Study to Evaluate CAD-1883 in Essential Tremor
NCT03780426	PHASE2	COMPLETED	tSMS in Essential Tremor
NCT04305275	PHASE2	COMPLETED	A Study to Evaluate the Efficacy, Safety, and Tolerability of SAGE-324 in Participants With Essential Tremor
NCT04727658	PHASE2	TERMINATED	Linac FRACtionated Radiosurgical THALamotomie in Tremors (FRACTHAL)
NCT04880616	PHASE2	COMPLETED	Safety, Efficacy, and Tolerability of NBI-827104 for the Treatment of Essential Tremor
NCT05021978	PHASE2	COMPLETED	A Clinical Trial of PRAX-944 in Participants With Essential Tremor
NCT05021991	PHASE2	COMPLETED	A Clinical Trial of 2 Doses of PRAX-944 in Participants With Essential Tremor
NCT05122650	PHASE2	COMPLETED	A Study To Assess the Safety and Efficacy of JZP385 in the Treatment of Adults With Moderate to Severe Essential Tremor (ET)
NCT05173012	PHASE2	COMPLETED	Study to Evaluate SAGE-324 in Participants With Essential Tremor
NCT05387642	PHASE2	WITHDRAWN	A Clinical Trial of PRAX-114 in Participants With Essential Tremor
NCT06312800	PHASE2	WITHDRAWN	Acamprosate and Methazolamide for Essential Tremor
NCT06821906	PHASE2	RECRUITING	Stereotactic Radiosurgery in the Treatment of Essential Tremor
NCT07074002	PHASE2	RECRUITING	Proof of Concept Study on BP1.4979 Effect on Essential Tremor
NCT07103265	PHASE2	NOT_YET_RECRUITING	Developing a New LIFU Neuromodulation Method to Suppress Tremor
NCT00001986	PHASE1	COMPLETED	1-Octanol to Treat Essential Tremor
NCT00016679	PHASE1	COMPLETED	1-Octanol to Treat Essential Tremor
NCT01304758	PHASE1	COMPLETED	ExAblate Transcranial MR Guided Focused Ultrasound in the Treatment of Essential Tremor