Amelogenesis imperfecta type 1

Summary

Amelogenesis imperfecta type 1 (MONDO:0015047) is a disease (an umbrella term covering 6 Mondo subtypes) caused by ENAM (GenCC Strong), with 8 cohort genes. The dominant Reactome pathway is Anchoring fibril formation (3 cohort genes).

At a glance

• Causal gene: ENAM (GenCC Strong)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 8
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amelogenesis imperfecta type 1
Mondo ID	MONDO:0015047
Orphanet	100031
SNOMED CT	109476006
UMLS	C0399367
MedGen	97992
GARD	0000645
Is cancer (heuristic)	no

Also known as: hypoplastic amelogenesis imperfecta

Data availability: 5 ClinVar variants · 7 GenCC gene-disease records.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › amelogenesis imperfecta › amelogenesis imperfecta type 1

Related subtypes (6): hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, amelogenesis imperfecta type 1G, X-linked amelogenesis imperfecta hypoplastic/hypomaturation 2, amelogenesis imperfecta type 2, amelogenesis imperfecta, IIa 1K, hypocalcified amelogenesis imperfecta

Subtypes (6): amelogenesis imperfecta type 1B, amelogenesis imperfecta type 1A, amelogenesis imperfecta type 1C, amelogenesis imperfecta type 1H, amelogenesis imperfecta type 1F, amelogenesis imperfecta, type 1J

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

5 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2082798	NM_000094.4(COL7A1):c.3785T>C (p.Met1262Thr)	COL7A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713936	NM_000094.4(COL7A1):c.3605G>A (p.Arg1202His)	COL7A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290568	NM_005562.3(LAMC2):c.493C>T (p.Arg165Cys)	LAMC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374862	NM_033068.3(ACP4):c.713C>T (p.Ser238Leu)	ACP4	Uncertain significance	criteria provided, single submitter
2444855	NM_000094.4(COL7A1):c.2440+3A>C	COL7A1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 37 · Orphanet: 21 · 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
ENAM	Definitive	Autosomal dominant	amelogenesis imperfecta type 1B	7
ACP4	Strong	Autosomal recessive	amelogenesis imperfecta, type 1J	2
AMBN	Strong	Autosomal recessive	amelogenesis imperfecta type 1F	4
ITGB6	Strong	Autosomal recessive	amelogenesis imperfecta type 1H	4
LAMB3	Strong	Autosomal dominant	amelogenesis imperfecta type 1A	15
RELT	Strong	Autosomal recessive	amelogenesis imperfecta, type 3C	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACP4	Orphanet:100031	Hypoplastic amelogenesis imperfecta
RELT	Orphanet:100032	Hypocalcified amelogenesis imperfecta
ENAM	Orphanet:100031	Hypoplastic amelogenesis imperfecta
AMBN	Orphanet:100031	Hypoplastic amelogenesis imperfecta
ITGB6	Orphanet:100031	Hypoplastic amelogenesis imperfecta
ITGB6	Orphanet:100032	Hypocalcified amelogenesis imperfecta
ITGB6	Orphanet:2850	Alopecia-intellectual disability syndrome
LAMB3	Orphanet:100031	Hypoplastic amelogenesis imperfecta
LAMB3	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
LAMB3	Orphanet:79404	Severe generalized junctional epidermolysis bullosa
COL7A1	Orphanet:158673	Localized dystrophic epidermolysis bullosa, acral form
COL7A1	Orphanet:158676	Localized dystrophic epidermolysis bullosa, nails only
COL7A1	Orphanet:231568	Autosomal dominant generalized dystrophic epidermolysis bullosa
COL7A1	Orphanet:79408	Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form
COL7A1	Orphanet:79409	Recessive dystrophic epidermolysis bullosa inversa
COL7A1	Orphanet:79410	Localized dystrophic epidermolysis bullosa, pretibial form
COL7A1	Orphanet:79411	Self-improving dystrophic epidermolysis bullosa
COL7A1	Orphanet:89842	Autosomal recessive generalized dystrophic epidermolysis bullosa, intermediate form
COL7A1	Orphanet:89843	Dystrophic epidermolysis bullosa pruriginosa
LAMC2	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
LAMC2	Orphanet:79404	Severe generalized junctional epidermolysis bullosa

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACP4	HGNC:14376	ENSG00000142513	Q9BZG2	Testicular acid phosphatase	gencc,clinvar
RELT	HGNC:13764	ENSG00000054967	Q969Z4	Tumor necrosis factor receptor superfamily member 19L	gencc
ENAM	HGNC:3344	ENSG00000132464	Q9NRM1	Enamelin	gencc
AMBN	HGNC:452	ENSG00000178522	Q9NP70	Ameloblastin	gencc
ITGB6	HGNC:6161	ENSG00000115221	P18564	Integrin beta-6	gencc
LAMB3	HGNC:6490	ENSG00000196878	Q13751	Laminin subunit beta-3	gencc
COL7A1	HGNC:2214	ENSG00000114270	Q02388	Collagen alpha-1(VII) chain	clinvar
LAMC2	HGNC:6493	ENSG00000058085	Q13753	Laminin subunit gamma-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACP4	Testicular acid phosphatase	May dephosphorylate receptor tyrosine-protein kinase ERBB4 and inhibits its ligand-induced proteolytic cleavage.
RELT	Tumor necrosis factor receptor superfamily member 19L	May play a role in apoptosis.
ENAM	Enamelin	Involved in the mineralization and structural organization of enamel.
AMBN	Ameloblastin	Involved in the mineralization and structural organization of enamel.
ITGB6	Integrin beta-6	Integrin alpha-V:beta-6 (ITGAV:ITGB6) is a receptor for fibronectin and cytotactin.
LAMB3	Laminin subunit beta-3	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
COL7A1	Collagen alpha-1(VII) chain	Stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV c…
LAMC2	Laminin subunit gamma-2	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 6 · Druggable fraction: 0.25

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
Phosphatase	1	10.5×	0.243
Antibody/Immunoglobulin	1	3.6×	0.243
Other/Unknown	6	1.3×	0.243

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACP4	Phosphatase	yes		His_Pase_clade-2, His_PPase_superfam, Acid_Pase_AS
RELT	Other/Unknown	no		TNF_rcpt_RELT, TNFR_19-like, TNFRSF19L_N
ENAM	Other/Unknown	no		Enamelin
AMBN	Other/Unknown	no		Amelin
ITGB6	Other/Unknown	no		Integrin_bsu_VWA, Integrin_bsu_tail, EGF_extracell
LAMB3	Other/Unknown	no		EGF, LE_dom, Laminin_N
COL7A1	Antibody/Immunoglobulin	yes		VWF_A, Kunitz_BPTI, FN3_dom
LAMC2	Other/Unknown	no		Laminin_IV, EGF, LE_dom

Expression context

Cohort genes with no expression data: 0.

7 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
periodontal ligament	3
male germ line stem cell (sensu Vertebrata) in testis	2
buccal mucosa cell	1
tendon of biceps brachii	1
tibialis anterior	1
granulocyte	1
leukocyte	1
monocyte	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
diaphragm	1
biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
visceral pleura	1
cartilage tissue	1
gingival epithelium	1
skin of abdomen	1
skin of leg	1
stromal cell of endometrium	1
hair follicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACP4	99		yes	tendon of biceps brachii, buccal mucosa cell, tibialis anterior
RELT	191	ubiquitous	marker	monocyte, leukocyte, granulocyte
ENAM	83	tissue_specific	marker	left ventricle myocardium, cardiac muscle of right atrium, male germ line stem cell (sensu Vertebrata) in testis
AMBN	32	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, periodontal ligament, diaphragm
ITGB6	188	broad	marker	visceral pleura, biceps brachii, skeletal muscle tissue of rectus abdominis
LAMB3	215	ubiquitous	marker	cartilage tissue, periodontal ligament, gingival epithelium
COL7A1	267	ubiquitous	marker	stromal cell of endometrium, skin of abdomen, skin of leg
LAMC2	209	broad	marker	islet of Langerhans, hair follicle, periodontal ligament

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LAMC2	2,061
COL7A1	1,767
LAMB3	1,697
ITGB6	1,461
AMBN	1,348
RELT	1,180
ENAM	1,001
ACP4	649

Intra-cohort edges

A	B	Sources
ACP4	AMBN	string_interaction
ACP4	ENAM	string_interaction
AMBN	ENAM	string_interaction
COL7A1	LAMB3	biogrid_interaction, string_interaction
COL7A1	LAMC2	biogrid_interaction, string_interaction
ENAM	LAMB3	string_interaction
LAMB3	LAMC2	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 7 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ITGB6	P18564	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACP4	Q9BZG2	88.30
LAMB3	Q13751	78.55
LAMC2	Q13753	72.89
RELT	Q969Z4	63.38
AMBN	Q9NP70	44.05
ENAM	Q9NRM1	36.63
COL7A1	Q02388

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 8 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Anchoring fibril formation	3	380.7×	1e-06	COL7A1, LAMB3, LAMC2
Laminin interactions	3	190.3×	6e-06	COL7A1, LAMB3, LAMC2
Assembly of collagen fibrils and other multimeric structures	3	100.2×	3e-05	COL7A1, LAMB3, LAMC2
Type I hemidesmosome assembly	2	346.1×	1e-04	LAMB3, LAMC2
MET promotes cell motility	2	200.3×	3e-04	LAMB3, LAMC2
Attachment of bacteria to epithelial cells	2	165.5×	3e-04	LAMB3, LAMC2
Collagen formation	2	152.3×	3e-04	LAMB3, LAMC2
Extracellular matrix organization	3	31.6×	3e-04	ITGB6, LAMB3, LAMC2
MET activates PTK2 signaling	2	126.9×	4e-04	LAMB3, LAMC2
Signaling by MET	2	105.7×	5e-04	LAMB3, LAMC2
Formation of the dystrophin-glycoprotein complex (DGC)	2	102.9×	5e-04	LAMB3, LAMC2
Developmental Lineage of Pancreatic Ductal Cells	2	76.1×	8e-04	LAMB3, LAMC2
Cell junction organization	2	62.4×	0.001	LAMB3, LAMC2
Non-integrin membrane-ECM interactions	2	51.4×	0.002	LAMB3, LAMC2
Cell-Cell communication	2	45.9×	0.002	LAMB3, LAMC2
Integrin cell surface interactions	2	44.8×	0.002	COL7A1, ITGB6
Degradation of the extracellular matrix	2	39.2×	0.002	LAMB3, LAMC2
Post-translational protein phosphorylation	2	33.4×	0.003	ENAM, AMBN
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	2	28.8×	0.004	ENAM, AMBN
Signaling by Receptor Tyrosine Kinases	2	17.2×	0.009	LAMB3, LAMC2
Fibronectin matrix formation	1	95.2×	0.017	COL7A1
Signal Transduction	3	5.1×	0.024	ITGB6, LAMB3, LAMC2
Elastic fibre formation	1	56.0×	0.026	ITGB6
Cargo concentration in the ER	1	56.0×	0.026	COL7A1
TGF-beta receptor signaling activates SMADs	1	54.4×	0.026	ITGB6
Molecules associated with elastic fibres	1	51.4×	0.026	ITGB6
Collagen chain trimerization	1	43.3×	0.030	COL7A1
Signaling by TGF-beta Receptor Complex	1	33.4×	0.037	ITGB6
Collagen degradation	1	29.3×	0.040	COL7A1
Collagen biosynthesis and modifying enzymes	1	28.4×	0.040	COL7A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
amelogenesis	3	526.6×	6e-07	RELT, ENAM, ITGB6
cell adhesion	5	23.4×	1e-05	COL7A1, AMBN, ITGB6, LAMB3, LAMC2
epidermis development	3	79.0×	8e-05	COL7A1, LAMB3, LAMC2
biomineral tissue development	2	162.0×	7e-04	ENAM, AMBN
endodermal cell differentiation	2	123.9×	9e-04	COL7A1, LAMB3
negative regulation of ERBB4 signaling pathway	1	2106.5×	0.003	ACP4
peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity	1	2106.5×	0.003	ACP4
transforming growth factor beta production	1	1053.2×	0.005	ITGB6
memory T cell differentiation	1	702.2×	0.006	ITGB6
Langerhans cell differentiation	1	526.6×	0.008	ITGB6
bronchiole development	1	421.3×	0.008	ITGB6
positive regulation of enamel mineralization	1	421.3×	0.008	ENAM
ameloblast differentiation	1	263.3×	0.012	ENAM
hard palate development	1	210.7×	0.014	ITGB6
enamel mineralization	1	150.5×	0.018	ITGB6
negative regulation of protein processing	1	140.4×	0.018	ACP4
phospholipid homeostasis	1	123.9×	0.019	ITGB6
surfactant homeostasis	1	100.3×	0.023	ITGB6
cell adhesion mediated by integrin	1	84.3×	0.024	ITGB6
regulation of neuronal synaptic plasticity	1	84.3×	0.024	ACP4
odontogenesis	1	65.8×	0.029	ACP4
skin development	1	55.4×	0.033	ITGB6
brown fat cell differentiation	1	54.0×	0.033	LAMB3
cellular response to ionizing radiation	1	51.4×	0.033	ITGB6
lung alveolus development	1	43.9×	0.037	ITGB6
odontogenesis of dentin-containing tooth	1	37.6×	0.041	AMBN
bone development	1	34.5×	0.043	ITGB6
negative regulation of neuron projection development	1	29.7×	0.049	ACP4
wound healing	1	28.5×	0.049	ITGB6
cell-matrix adhesion	1	20.4×	0.062	ITGB6

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 4 of 8 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ITGB6	5	3
ACP4	0	0
RELT	0	0
ENAM	0	0
AMBN	0	0
LAMB3	0	0
COL7A1	0	0
LAMC2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CILENGITIDE	3	ITGB6
NESVATEGRAST	2	ITGB6
GLPG-0187	1	ITGB6
GSK-3008348 FREE BASE	1	ITGB6
GSK-3008348	1	ITGB6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ITGB6	79	Binding:75, ADMET:2, Functional:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

5 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.

Compound	Max phase	Cohort target (bioactivity)
CILENGITIDE	3	ITGB6
NESVATEGRAST	2	ITGB6
GLPG-0187	1	ITGB6
GSK-3008348 FREE BASE	1	ITGB6
GSK-3008348	1	ITGB6

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	1	ITGB6
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	ACP4, COL7A1
E	Difficult family or no structure, no drug	5	RELT, ENAM, AMBN, LAMB3, LAMC2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACP4	0	—
RELT	0	—
ENAM	0	—
AMBN	0	—
LAMB3	0	—
COL7A1	0	—
LAMC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.