Hemochromatosis type 3

Summary

Hemochromatosis type 3 (MONDO:0011417) is a disease caused by TFR2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TFR2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 327

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		33	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hemochromatosis type 3
Mondo ID	MONDO:0011417
MeSH	C537248
OMIM	604250
Orphanet	225123
DOID	DOID:0111030
SNOMED CT	719974003
UMLS	C1858664
MedGen	388114
GARD	0010093
Is cancer (heuristic)	no

Also known as: hemochromatosis type 3 · hemochromatosis, type 3 · hereditary hemochromatosis caused by mutation in TFR2 · HFE3 · TFR2 hereditary hemochromatosis · TFR2-related hemochromatosis

Data availability: 327 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › iron metabolism disease › hemosiderosis › hereditary hemochromatosis › hemochromatosis type 3

Related subtypes (7): neonatal hemochromatosis, African iron overload, hemochromatosis type 4, hemochromatosis type 5, hemochromatosis type 2, hemochromatosis type 1, digenic hemochromatosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

327 retrieved; paginated sample, class counts are floors:

95 uncertain significance, 73 likely pathogenic, 47 conflicting classifications of pathogenicity, 47 likely benign, 31 pathogenic/likely pathogenic, 12 pathogenic, 10 benign, 6 not provided, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075084	NM_003227.4(TFR2):c.2095_2096del (p.Asp699fs)	LOC113687175	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405162	NM_003227.4(TFR2):c.2136+1G>A	LOC113687175	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1417753	NM_003227.4(TFR2):c.2092A>T (p.Arg698Ter)	LOC113687175	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2438477	NM_003227.4(TFR2):c.2093_2096del (p.Arg698fs)	LOC113687175	Pathogenic	criteria provided, multiple submitters, no conflicts
2971822	NM_003227.4(TFR2):c.2096_2100del (p.Asp699fs)	LOC113687175	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632495	NM_003227.4(TFR2):c.2014C>T (p.Gln672Ter)	LOC113687175	Pathogenic	criteria provided, multiple submitters, no conflicts
802342	NM_003227.4(TFR2):c.2101C>T (p.Arg701Ter)	LOC113687175	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
839335	NM_003227.4(TFR2):c.2025C>G (p.Tyr675Ter)	LOC113687175	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
854136	NM_003227.4(TFR2):c.2038dup (p.Asp680fs)	LOC113687175	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
961267	NM_003227.4(TFR2):c.2128_2132del (p.Ile710fs)	LOC113687175	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072553	NM_003227.4(TFR2):c.2236dup (p.Asp746fs)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072555	NM_003227.4(TFR2):c.405_406del (p.Tyr136fs)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073644	NM_003227.4(TFR2):c.862C>T (p.Gln288Ter)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076276	NM_003227.4(TFR2):c.661G>T (p.Gly221Ter)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323686	NM_003227.4(TFR2):c.1768-1G>A	TFR2	Pathogenic	criteria provided, single submitter
1389891	NM_003227.4(TFR2):c.33+1del	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1431727	NM_003227.4(TFR2):c.34C>T (p.Gln12Ter)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1440812	NM_003227.4(TFR2):c.2227_2228del (p.Ala743fs)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1926610	NM_003227.4(TFR2):c.1470del (p.Glu491fs)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1994247	NM_003227.4(TFR2):c.58C>T (p.Gln20Ter)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2024923	NM_003227.4(TFR2):c.63_66del (p.Val22fs)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21362	NM_003227.4(TFR2):c.1186C>T (p.Arg396Ter)	TFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
21370	NM_003227.4(TFR2):c.1849GCCGTGGCCCAG[1] (p.617AVAQ[1])	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21375	NM_003227.4(TFR2):c.313C>T (p.Arg105Ter)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2143093	NM_003227.4(TFR2):c.523_524del (p.Leu175fs)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2418037	NM_003227.4(TFR2):c.1071_1075del (p.Gln357fs)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679169	NM_003227.4(TFR2):c.1467G>A (p.Trp489Ter)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2786414	NM_003227.4(TFR2):c.124del (p.Glu42fs)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4062174	NM_003227.4(TFR2):c.1538-2A>G	TFR2	Pathogenic	criteria provided, single submitter
461197	NM_003227.4(TFR2):c.1398del (p.Arg468fs)	TFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TFR2	Definitive	Autosomal recessive	hemochromatosis type 3	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TFR2	Orphanet:225123	TFR2-related hemochromatosis
TFR2	Orphanet:648581	Digenic hemochromatosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TFR2	HGNC:11762	ENSG00000106327	Q9UP52	Transferrin receptor protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TFR2	Transferrin receptor protein 2	Mediates cellular uptake of transferrin-bound iron in a non-iron dependent manner.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TFR2	Protease	yes		PA_domain, Peptidase_M28, TFR-like_dimer_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
right lobe of liver	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TFR2	188	tissue_specific	marker	right lobe of liver, liver, vena cava

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TFR2	1,077

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TFR2	Q9UP52	83.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transferrin endocytosis and recycling	1	368.4×	0.004	TFR2
Iron uptake and transport	1	346.1×	0.004	TFR2
Transport of small molecules	1	25.1×	0.040	TFR2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
endocytic iron import into cell	1	16852.0×	4e-04	TFR2
positive regulation of protein maturation	1	16852.0×	4e-04	TFR2
cellular response to iron ion	1	2407.4×	0.002	TFR2
transferrin transport	1	1532.0×	0.002	TFR2
positive regulation of peptide hormone secretion	1	1532.0×	0.002	TFR2
response to iron ion	1	936.2×	0.002	TFR2
iron ion transport	1	887.0×	0.002	TFR2
positive regulation of endocytosis	1	802.5×	0.002	TFR2
multicellular organismal-level iron ion homeostasis	1	581.1×	0.002	TFR2
intracellular iron ion homeostasis	1	244.2×	0.005	TFR2
receptor-mediated endocytosis	1	221.7×	0.005	TFR2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	TFR2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TFR2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	TFR2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TFR2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.