Hemochromatosis type 5

Summary

Hemochromatosis type 5 (MONDO:0014225) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hemochromatosis type 5
Mondo ID	MONDO:0014225
MeSH	C565020
OMIM	615517
Orphanet	247790, 447792
DOID	DOID:0111031
UMLS	C1851316
MedGen	341982
GARD	0013472
Is cancer (heuristic)	no

Also known as: FTH1 hereditary hemochromatosis · FTH1-associated iron overload · FTH1-related iron overload · hemochromatosis, type 5 · hereditary hemochromatosis caused by mutation in FTH1 · HFE5

Data availability: 19 ClinVar variants · 7 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 5

Related subtypes (7): neonatal hemochromatosis, African iron overload, hemochromatosis type 3, hemochromatosis type 4, 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

19 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 4 benign, 2 benign/likely benign, 1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
16490	NM_002032.3(FTH1):c.-164A>T	FTH1	Pathogenic	no assertion criteria provided
305135	NM_002032.3(FTH1):c.*389A>G	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305141	NM_002032.3(FTH1):c.413A>T (p.Tyr138Phe)	BEST1	Uncertain significance	criteria provided, single submitter
305144	NM_002032.3(FTH1):c.208C>T (p.Leu70=)	BEST1	Uncertain significance	criteria provided, single submitter
878748	NM_002032.3(FTH1):c.*159C>T	BEST1	Uncertain significance	criteria provided, single submitter
880474	NM_002032.3(FTH1):c.*336A>G	BEST1	Uncertain significance	criteria provided, single submitter
305134	NM_002032.3(FTH1):c.*396A>G	FTH1	Uncertain significance	criteria provided, single submitter
305138	NM_002032.3(FTH1):c.*312A>G	FTH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
305140	NM_002032.3(FTH1):c.*165T>C	FTH1	Uncertain significance	criteria provided, single submitter
305146	NM_002032.3(FTH1):c.-2C>T	FTH1	Uncertain significance	criteria provided, single submitter
879333	NM_002032.3(FTH1):c.-14C>T	FTH1	Uncertain significance	criteria provided, single submitter
879334	NM_002032.3(FTH1):c.-136C>A	FTH1	Uncertain significance	criteria provided, single submitter
305147	NM_002032.3(FTH1):c.-204A>G	LOC399900	Uncertain significance	criteria provided, single submitter
305137	NM_002032.3(FTH1):c.*319G>A	BEST1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
305139	NM_002032.3(FTH1):c.*222C>T	BEST1	Benign	criteria provided, multiple submitters, no conflicts
305142	NM_002032.3(FTH1):c.388-5T>C	BEST1	Benign	criteria provided, single submitter
305143	NM_002032.3(FTH1):c.387+12A>G	FTH1	Benign	criteria provided, multiple submitters, no conflicts
305145	NM_002032.3(FTH1):c.161A>G (p.Lys54Arg)	FTH1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
878749	NM_002032.3(FTH1):c.60C>T (p.Ala20=)	FTH1	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 9 · 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
FTH1	Moderate	Autosomal dominant	hemochromatosis type 5	9
BMP6	Supportive	Autosomal dominant	hemochromatosis type 5	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FTH1	Orphanet:247790	FTH1-related iron overload
BMP6	Orphanet:465508	Symptomatic form of HFE-related hemochromatosis
BEST1	Orphanet:1243	Best vitelliform macular dystrophy
BEST1	Orphanet:139455	Autosomal recessive bestrophinopathy
BEST1	Orphanet:263347	MRCS syndrome
BEST1	Orphanet:3086	Autosomal dominant vitreoretinochoroidopathy
BEST1	Orphanet:35612	Nanophthalmos
BEST1	Orphanet:791	Retinitis pigmentosa
BEST1	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FTH1	HGNC:3976	ENSG00000167996	P02794	Ferritin heavy chain	gencc,clinvar
BMP6	HGNC:1073	ENSG00000153162	P22004	Bone morphogenetic protein 6	gencc
BEST1	HGNC:12703	ENSG00000167995	O76090	Bestrophin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FTH1	Ferritin heavy chain	Stores iron in a soluble, non-toxic, readily available form.
BMP6	Bone morphogenetic protein 6	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes including cartilage and bone formation.
BEST1	Bestrophin-1	Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FTH1	Enzyme (other)	yes	1.16.3.1	Ferritin, Ferritin_DPS_dom, Ferritin-like_diiron
BMP6	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
BEST1	Other/Unknown	no		Bestrophin, Bestrophin-like

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
nerve	1
stromal cell of endometrium	1
upper lobe of left lung	1
cartilage tissue	1
oocyte	1
secondary oocyte	1
inferior olivary complex	1
lateral globus pallidus	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FTH1	292	ubiquitous	marker	stromal cell of endometrium, upper lobe of left lung, nerve
BMP6	197	ubiquitous	marker	secondary oocyte, cartilage tissue, oocyte
BEST1	209	ubiquitous	marker	pigmented layer of retina, lateral globus pallidus, inferior olivary complex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FTH1	2,729
BMP6	1,739
BEST1	959

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FTH1	P02794	147
BEST1	O76090	19
BMP6	P22004	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Scavenging by Class A Receptors	1	300.5×	0.020	FTH1
Iron uptake and transport	1	173.0×	0.020	FTH1
Golgi Associated Vesicle Biogenesis	1	100.2×	0.023	FTH1
Stimuli-sensing channels	1	68.0×	0.026	BEST1
Ion channel transport	1	48.0×	0.029	BEST1
Transport of small molecules	1	12.6×	0.085	BEST1
Neutrophil degranulation	1	11.5×	0.085	FTH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intracellular iron ion homeostasis	2	162.8×	0.003	FTH1, BMP6
gamma-aminobutyric acid secretion, neurotransmission	1	2808.7×	0.007	BEST1
negative regulation of adherens junction organization	1	2808.7×	0.007	BMP6
positive regulation of aldosterone biosynthetic process	1	1872.4×	0.008	BMP6
positive regulation of aldosterone secretion	1	1404.3×	0.008	BMP6
cellular response to iron ion	1	802.5×	0.009	BMP6
transepithelial chloride transport	1	624.1×	0.009	BEST1
glutamate secretion	1	561.7×	0.009	BEST1
positive regulation of lipopolysaccharide-mediated signaling pathway	1	510.7×	0.009	BMP6
positive regulation of endothelial cell differentiation	1	510.7×	0.009	BMP6
negative regulation of cell-cell adhesion mediated by cadherin	1	510.7×	0.009	BMP6
response to magnesium ion	1	468.1×	0.009	BMP6
type B pancreatic cell development	1	432.1×	0.009	BMP6
positive regulation of vascular permeability	1	432.1×	0.009	BMP6
immune response	2	31.4×	0.009	FTH1, BMP6
iron ion transport	1	295.6×	0.011	FTH1
male genitalia development	1	295.6×	0.011	BMP6
positive regulation of chondrocyte differentiation	1	267.5×	0.011	BMP6
regulation of calcium ion transport	1	267.5×	0.011	BEST1
negative regulation of ferroptosis	1	267.5×	0.011	FTH1
protein complex oligomerization	1	224.7×	0.012	BEST1
detection of light stimulus involved in visual perception	1	216.1×	0.012	BEST1
positive regulation of intracellular signal transduction	1	216.1×	0.012	BMP6
multicellular organismal-level iron ion homeostasis	1	193.7×	0.012	BMP6
cellular response to BMP stimulus	1	187.2×	0.012	BMP6
endochondral ossification	1	181.2×	0.012	BMP6
negative regulation of fibroblast proliferation	1	165.2×	0.013	FTH1
chloride transport	1	151.8×	0.014	BEST1
positive regulation of bone mineralization	1	130.6×	0.015	BMP6
response to retinoic acid	1	127.7×	0.015	BMP6

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FTH1	0	0
BMP6	0	0
BEST1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FTH1	2	Binding:2
BMP6	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FTH1	1.16.3.1	ferroxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	FTH1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	BMP6, BEST1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FTH1	2	—
BMP6	1	—
BEST1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.