TFR2

protein-coding

transferrin receptor 2, the group of M28 metallopeptidases

Gene summary

This gene encodes a single-pass type II membrane protein, which is a member of the transferrin receptor-like family. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation. Mutations in this gene have been associated with hereditary hemochromatosis type III. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2011]

MANE transcript

NM_003227.4

Inheritance

ClinVar variants

P:184U:221B:461

Top phenotype

Hemochromatosis, type 3

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr7:100,620,416-100,642,779

External References & Databases

Ensembl (ENSG00000106327)

Transcript & Mutation Effects

hg38 • Region Span ~22.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hemochromatosis type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011417

Submitter: PanelApp Australia

hemochromatosis type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011417

Submitter: Ambry Genetics

hemochromatosis type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011417

Submitter: ClinGen

The TFR2 gene encodes transferrin receptor 2, which is predominantly expressed in the liver. This receptor mediates the cellular uptake of transferrin-bound iron and plays a key role in the synthesis of hepcidin (PMID: 36483608). TFR2 was first implicated in autosomal recessive hemochromatosis type 3 (HH3) in 2000 (Camaschella et al., PMID: 10802645). HH3 is characterized by elevated transferrin saturation, serum ferritin, iron levels, and liver transaminases, along with increased hepatic iron deposition and decreased serum hepcidin. Clinical manifestations include cirrhosis, liver fibrosis, hepatosplenomegaly, cardiomyopathy, hyperpigmentation, hypogonadism, arthritis, diabetes, and hematological abnormalities. A variety of pathogenic variants have been reported in affected individuals, including missense, nonsense, splicing, frameshift variants, and in-frame deletions. This curation includes 25 unrelated probands and 24 unique variants (PMIDs: 10802645, 11313241, 11984516, 12130528, 15685557, 16923517, 18245657, 18450729, 19144662, 23600741, 26029709, 34946929, 35464850). The gene-disease relationship is supported by case-level data and segregation studies, reaching the maximum score of 12 points for case level evidence. Additional support comes from animal models, expression studies, and functional assays (PMIDs: 10409623, 12134060, 15951546, 18064142, 16935854, 20177050, 20179178, 26408288). Northern blot analysis of human tissues confirmed predominant liver expression of TFR2, and the protein was shown to bind iron-loaded transferrin to facilitate hepatic iron uptake (PMID: 10409623). Multiple TFR2 knockout (KO) mouse models recapitulate the human phenotype, including elevated transferrin saturation, iron levels, ferritin, and hepatic iron accumulation (PMIDs: 12134060, 16935854, 15951546, 20133002, 20179178). These models also exhibit dysregulation of iron metabolism genes coding for hepcidin and ferroportin (PMIDs: 16935854, 20179178, 20133002). Liver-specific knock-in of wild-type TFR2 rescued the iron overload phenotype and restored hepcidin expression (PMID: 20177050). In vitro studies demonstrated that variants identified in HH3 patients led to reduced TFR2 protein accumulation, abnormal glycosylation, retention of mutant proteins in the endoplasmic reticulum and absence of mutant protein on the cell membrane (PMIDs: 26029709, 18094142, 26408288). Although additional experimental evidence exists, the maximum score of 6 points for experimental evidence has already been reached. In summary, there is definitive evidence supporting the relationship between TFR2 and autosomal recessive hemochromatosis type 3. This association has been consistently demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on the meeting date August 22, 2025 (SOP Version 11).

hemochromatosis type 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011417

Submitter: Orphanet

hemochromatosis type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011417

Submitter: Natera

hemochromatosis type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011417

Submitter: G2P

hemochromatosis type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011417

Submitter: Labcorp Genetics (formerly Invitae)

hemochromatosis type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011417

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Hemochromatosis, type 3AR

Manifestation: Biochemical; Cardiovascular; Endocrine; Gastrointestinal; Hematologic

Intervention: Biochemical; Gastrointestinal; Hematologic

Rationale: Preventive measures and treatment of iron overload (by phlebotomy) can be beneficial

Comments: Variants may also modify hemochromatosis due to mutations in other genes (eg, HFE)

Refs: 10216143; 10802645; 12150153; 12130528; 19549277; 20542038; 21770687

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TFR2 variants in ClinVar

9 Conditions Cataloged

Hereditary hemochromatosisTotal: 918

Hemochromatosis type 3Total: 316

Inborn genetic diseasesTotal: 107

not providedTotal: 36

TFR2-related disorderTotal: 20

not specifiedTotal: 10

Hemochromatosis type 1Total: 2

Hemochromatosis, type 1, modifier ofTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003227.4. 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			14 clinvar	419 clinvar	4 clinvar	437
missense	3 clinvar	11 clinvar	200 clinvar	36 clinvar	1 clinvar	251
nonsense	15 clinvar	27 clinvar	1 clinvar			43
start loss			1 clinvar			1
frameshift	33 clinvar	49 clinvar	1 clinvar			83
splice donor/acceptor (+/-2bp)	4 clinvar	42 clinvar	4 clinvar	1 clinvar		51
Total	55	129	221	456	5	866

Highest pathogenic variant AF is 0.00008364551

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 173 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003227.4	RefSeq	NP_003218.2	18	MANE Select
ENST00000223051.8	Ensembl	ENSP00000223051.3	18	MANE Select
NM_001206855.3	RefSeq	NP_001193784.1	15	Standard
ENST00000431692.5	Ensembl	ENSP00000413905.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tfr2	Danio rerio	Structure: muscle Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

tfr2

Danio rerio

Structure: muscle

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Iron metabolism in placenta
Transferrin endocytosis and recycling
Transport of small molecules
Iron uptake and transport

Biological Process

iron ion transport
cellular iron ion homeostasis
receptor-mediated endocytosis
acute-phase response
response to iron ion

Molecular Function

transferrin receptor activity
protein binding
transferrin transmembrane transporter activity
co-receptor binding

Cellular Component

plasma membrane
integral component of plasma membrane
external side of plasma membrane
cytoplasmic vesicle
HFE-transferrin receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000462107
Coding exons: 18
Length: 22364
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 59
Defined: 125748
p: 0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.15	401	471	0.852	0.0000284	5109
Missense (PolyPhen)		127	170.18	0.74628		1801
Synonymous	1.18	184	206	0.895	0.0000132	1663
Loss of Function	2.72	21	39.4	0.533	0.00000191	416

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00023	0.00018	rare
Latino/Admixed American	0.00096	0.00095	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00012	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mediates cellular uptake of transferrin-bound iron in a non-iron dependent manner. May be involved in iron metabolism, hepatocyte function and erythrocyte differentiation.;

Intolerance Scores

LoFtool: 0.713
RVIS EVS: -0.53
RVIS percentile EVS: 20.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Indispensability pred.: E
Indispensability score: 0.887

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium