FTL
protein-codingferritin light chain, the group of Ferritin subunits
Gene summary
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. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~2.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014274
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014274
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0010952
Submitter: Genomics England PanelApp
Inheritance Pattern: Unknown
Disease ID:MONDO:0014274
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011638
Submitter: ClinGen
The *FTL* gene codes for the ferritin light chain. The *FTL* subunit of the ferritin enhances iron nucleation. It also protects the heteropolymer against aggregation and precipitation that may occur while incubating with Fe (II) during iron incorporation. Variants in *FTL* have been reported in individuals with Neurodegeneration with brain iron accumulation 3; NBIA3/Hereditary Neuroferritinopathy (NF)/Adult-onset basal ganglia disease (MIM# 606159). The disease displays autosomal dominant inheritance. Linkage analysis and Haplotype analysis was conducted in one publication (PMID: 11438811) led to sequencing of the FTL gene. and published LOD score included in the scoring. Summary of case-based evidence: 10 variants, with 9 duplications (frameshift variants) and one substitution have been documented. The frameshift variants in exon 4, affect the C-terminal sequence. This causes disordered four-fold pores allowing iron leakage and enhanced formation of toxic, improperly coordinated iron. (PMIDs: 16116125, 15099026, 19514068, 18854324, 11438811, 22818529, 15835264, 19117339, 24825732, 18413574, 24907184, 25809671). Summary of experimental evidence: This gene-disease association is supported by experimental evidence from the study on apoferritin when subjected to high iron increments, heteropolymers of ferritin with L:H ratios are highly efficient in incorporating iron (PMID: 8182740). The studies in the transgenic FVB-mouse model expressing the pathogenic human FTL mutant c.498InsTC under the PGK promoter, confirmed the presence of ferritin/iron bodies in most tissues, principally in the brain: the main hallmark of the neuroferritinopathy patients and of the reported neuroferritinopathy mouse model (PMID: 25689865, 25447222). Further, in a second transgenic mouse model study (PMID: 19519778), homozygous FTL-Tg mice (FTL-Tg 4) expressing the variant (c.498-499InsTC) showed the presence of ferritin nuclear inclusions in the brain. Functional studies (PMID: 18755684): Analysis of recombinant WT- and MT-FTL (mutant p.Phe167SerfsX26) polypeptides expressed in E. coli suggest that, since the C terminus is exposed external to the protein shell in the MT-FTL, these homopolymers have a diminished ability to sequester iron and show enhanced aggregation compared to wild type homopolymers, as iron levels are increased. Expression study (PMID: 20159981), where analysis of mutant ferritins (L148fs, L154fs, L167fs) expressed in transfected E. coli cells was studied for iron incorporation as both homopolymers and heteropolymers along with H-ferritin. It was observed that the mutant ferritin incorporated little iron when supplied in ferrous or ferric forms. In summary, there is definitive evidence to support the relationship between variants in the *FTL* gene and Neuroferritinopathy. Further, biochemical studies (PMID: 21029774), demonstrated that the *in vitro* functional problems characterized in mutant-containing ferritin heteropolymers in the study, support a connection to demonstrated cellular abnormalities in patients with HF and in an animal model consistent with both a loss of normal function and a gain of toxic function of ferritin. In summary, there is definitive evidence to support the relationship between variants in the *FTL* gene and Hereditary neuroferritinopathy. This classification was approved by the ClinGen IEM GCEP on June 12th, 2026 (SOP Version 12).
Inheritance Pattern: AD
Disease ID:MONDO:0011638
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0010952
Submitter: ClinGen
The *FTL* gene codes for the ferritin light chain. Synthesis of both heavy H- type and light L- type ferritin subunits is controlled by a common cytosolic protein known as iron regulatory protein (IRP), which binds to the iron-responsive element (IRE) in the 5′-UTR of the H- and L-ferritin mRNAs (PMID:11389486). The L-ferritin subunit helps with electron transport in and out of the ferritin core protein and plays a role in iron release, as Fe+2, from ferritin and storage of iron in a soluble, non-toxic, readily available form. Variants in *FTL* have been reported in individuals with Hereditary Hyperferritinemia cataract syndrome (HHCS) (MIM#600886). The disease displays autosomal dominant inheritance with incomplete penetrance and can occur with isolated hyperferritinemia. Summary of case-based evidence: 23 variants, with 20 substitutions and 3 deletions have been documented with variants affecting upper stem, lower stem, C-bulge, hexanucleotide loop *FTL* mRNA IRE hair pin which disrupt its specific interaction and optimal binding with the cytoplasmic iron regulatory protein (IRP) leading to failure of suppression of L-ferritin translation. (PMIDs: 16518306, 22881709, 24983587,18710380, 9414313, 9292547, 21410535, ,24766965, 28636169, 26849797, 15690351, 21569394, 15234655, 29269865, 10366804, 15861269, 41300832, 24936091, 19887780, 21410535, 15223007, 23421845, 10759702, 7493028, 11923255). Haplotype analysis was conducted in three publications (PMID: 16518306, 27096259, 23592921) and published LOD scores included in the scoring. Summary of experimental evidence: This gene-disease association is supported by experimental evidence from the study on apoferritin when subjected to high iron increments, heteropolymers of ferritin with L:H ratios are highly efficient in incorporating iron (PMID: 8182740) . Further, it was observed that on using CRISPR-Cas9 genome editing to delete the endogenous eIF3 interaction site in FTL (human eukaryotic translation initiation factor 3 (eIF3) acts as a distinct repressor of FTL mRNA translation) disruption of eIF3 interactions with FTL mRNA due to specific variants in the *FTL* 5’- UTR likely contributes to a subset of hyperferritinemia cases (PMID:31414986). Another study on plasmid constructs with the IRE region of L-Ferritin, computer modelling and nuclease mapping experiments have indicated IRE forms the central part of a large stem-and-loop structure near the 5’-end of ferritin mRNAs. Mutations that disrupt the base-pairing in the upper stem, alter the IRE-BP binding by causing a kink in the RNA helix (PMID: 1644834). Experimental studies measuring the ability of the mutant IREs to compete with radiolabelled wild-type L-ferritin IRE *in vitro* using band-shift competition assays were used to study correlation between binding affinity with clinical severity (PMID:10473603). Expression studies of human *FTL* and its mouse counterpart in the lens, detected RT–PCR amplicons containing full-length protein-coding regions and strong *in situ* localization of FTL1 transcripts to the lens equatorial epithelium and peripheral cortex (PMID: 23592921). In summary, there is definitive evidence to support the relationship between variants in the *FTL* gene and Hereditary Hyperferritinemia cataract syndrome. This classification was approved by the ClinGen IEM GCEP on January 23, 2026 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0016788
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010952
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0010952
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011638
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0010952
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011638
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010952
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011638
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Hematologic; Neurologic; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FTL variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000146.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 5 | 21 | 1 | 27 | ||
| missense | 1 | 2 | 76 | 4 | 83 | |
| nonsense | 2 | 3 | 5 | |||
| start loss | 1 | 1 | 2 | |||
| frameshift | 6 | 4 | 7 | 17 | ||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 3 | |||
| Total | 9 | 9 | 93 | 25 | 1 | 137 |
Highest pathogenic variant AF is 0.000015058654
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000137.2 | 4 | MANE Select | |
| Ensembl | ENSP00000366525.2 | 4 | MANE Select | |
| Ensembl | ENSP00000520709.1 | 3 | Standard | |
| Ensembl | ENSP00000520709.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Necroptosis - Homo sapiens (human)
- Mineral absorption - Homo sapiens (human)
- Ferroptosis - Homo sapiens (human)
- Nuclear Receptors Meta-Pathway
- NRF2 pathway
Biological Process
- iron ion transport
- cellular iron ion homeostasis
- intracellular sequestering of iron ion
- neutrophil degranulation
- iron ion homeostasis
Molecular Function
- ferroxidase activity
- iron ion binding
- protein binding
- ferrous iron binding
- ferric iron binding
Cellular Component
- extracellular region
- cytoplasm
- cytosol
- intracellular ferritin complex
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000331825
- Coding exons
- 4
- Length
- 1578
- Individuals with no LoFs
- 125720
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 28
- Defined
- 125748
- p
- 0.000111
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.441 | 106 | 94.0 | 1.13 | 0.00000513 | 1158 |
| Missense (PolyPhen) | 11 | 12.858 | 0.85548 | 231 | ||
| Synonymous | 0.0635 | 40 | 40.5 | 0.987 | 0.00000233 | 337 |
| Loss of Function | -1.51 | 11 | 6.77 | 1.62 | 2.94e-7 | 85 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00043 | 0.00043 | rare |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.00023 | 0.00023 | rare |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- 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 (By similarity). {ECO:0000250, ECO:0000269|PubMed:19923220, ECO:0000269|PubMed:20159981}.;
- Disease
- DISEASE: 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. {ECO:0000269|PubMed:19176363}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:16116125}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:23940258}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.648
Intolerance Scores
- LoFtool
- 0.791
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 41.25
Essentials
- Essential (CRISPR)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.955
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |