Amelogenesis imperfecta type 2

Summary

Amelogenesis imperfecta type 2 (MONDO:0015048) is a disease (an umbrella term covering 7 Mondo subtypes) with 7 cohort genes.

At a glance

• Umbrella term: 7 Mondo subtypes
• Cohort genes: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amelogenesis imperfecta type 2
Mondo ID	MONDO:0015048
MeSH	C536606
Orphanet	100033
SNOMED CT	109475005
UMLS	C0399372
MedGen	97994
GARD	0008349
Is cancer (heuristic)	no

Also known as: amelogenesis imperfecta hypomaturation type · hypomaturation amelogenesis imperfecta

Data availability: 7 GenCC gene-disease records.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › amelogenesis imperfecta › amelogenesis imperfecta type 2

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

Subtypes (7): amelogenesis imperfecta type 2A1, amelogenesis imperfecta type 1E, amelogenesis imperfecta hypomaturation type 2A2, amelogenesis imperfecta hypomaturation type 2A3, amelogenesis imperfecta hypomaturation type 2A4, amelogenesis imperfecta hypomaturation type 2A5, amelogenesis imperfecta, hypomaturation type, IIa6

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · 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
AMELX	Strong	X-linked	amelogenesis imperfecta type 1E	4
GPR68	Strong	Autosomal recessive	amelogenesis imperfecta, hypomaturation type, IIa6	4
KLK4	Strong	Autosomal recessive	amelogenesis imperfecta type 2A1	4
MMP20	Strong	Autosomal recessive	amelogenesis imperfecta hypomaturation type 2A2	4
ODAPH	Strong	Autosomal recessive	amelogenesis imperfecta hypomaturation type 2A4	4
SLC24A4	Strong	Autosomal recessive	amelogenesis imperfecta hypomaturation type 2A5	6
WDR72	Strong	Autosomal recessive	amelogenesis imperfecta hypomaturation type 2A3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC24A4	Orphanet:100032	Hypocalcified amelogenesis imperfecta
SLC24A4	Orphanet:100033	Hypomaturation amelogenesis imperfecta
ODAPH	Orphanet:100033	Hypomaturation amelogenesis imperfecta
WDR72	Orphanet:100033	Hypomaturation amelogenesis imperfecta
WDR72	Orphanet:402041	Autosomal recessive distal renal tubular acidosis
GPR68	Orphanet:100033	Hypomaturation amelogenesis imperfecta
AMELX	Orphanet:100033	Hypomaturation amelogenesis imperfecta
KLK4	Orphanet:100033	Hypomaturation amelogenesis imperfecta
MMP20	Orphanet:100033	Hypomaturation amelogenesis imperfecta

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC24A4	HGNC:10978	ENSG00000140090	Q8NFF2	Sodium/potassium/calcium exchanger 4	gencc
ODAPH	HGNC:26300	ENSG00000174792	Q17RF5	Odontogenesis associated phosphoprotein	gencc
WDR72	HGNC:26790	ENSG00000166415	Q3MJ13	WD repeat-containing protein 72	gencc
GPR68	HGNC:4519	ENSG00000119714	Q15743	G-protein coupled receptor 68	gencc
AMELX	HGNC:461	ENSG00000125363	Q99217	Amelogenin, X isoform	gencc
KLK4	HGNC:6365	ENSG00000167749	Q9Y5K2	Kallikrein-4	gencc
MMP20	HGNC:7167	ENSG00000137674	O60882	Matrix metalloproteinase-20	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC24A4	Sodium/potassium/calcium exchanger 4	Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+).
ODAPH	Odontogenesis associated phosphoprotein	May promote nucleation of hydroxyapatite.
WDR72	WD repeat-containing protein 72	Plays a major role in formation of tooth enamel.
GPR68	G-protein coupled receptor 68	Proton-sensing G-protein coupled receptor activated by extracellular pH, which is required to monitor pH changes and generate adaptive reactions.
AMELX	Amelogenin, X isoform	Plays a role in biomineralization.
KLK4	Kallikrein-4	Has a major role in enamel formation.
MMP20	Matrix metalloproteinase-20	Degrades amelogenin, the major protein component of the enamel matrix and two of the macromolecules characterizing the cartilage extracellular matrix: aggrecan and the cartilage oligomeric matrix protein (COMP).

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.43

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	2	10.5×	0.057
GPCR	1	3.4×	0.455
Scaffold/PPI	1	2.5×	0.455
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC24A4	Other/Unknown	no		K/Na/Ca-exchanger, NaCa_Exmemb, NCX_ion-bd_dom_sf
ODAPH	Other/Unknown	no		ODAPH
WDR72	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
GPR68	GPCR	yes		GPCR_Rhodpsn, OGR1_rcpt, GPCR_Rhodpsn_7TM
AMELX	Other/Unknown	no		Amelogenin
KLK4	Protease	yes	3.4.21.B12	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
MMP20	Protease	yes	3.4.24.B6	Hemopexin-like_dom, Pept_M10_metallopeptidase, Peptidoglycan-bd-like

Expression context

Cohort genes with no expression data: 0.

4 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
kidney epithelium	2
leukocyte	1
monocyte	1
primary visual cortex	1
buccal mucosa cell	1
placenta	1
pancreatic ductal cell	1
renal medulla	1
gingival epithelium	1
granulocyte	1
tendon of biceps brachii	1
frontal pole	1
paraflocculus	1
lower esophagus mucosa	1
prostate gland	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC24A4	168	broad	marker	monocyte, leukocyte, primary visual cortex
ODAPH	153	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell, placenta
WDR72	139	tissue_specific	marker	kidney epithelium, pancreatic ductal cell, renal medulla
GPR68	203	broad	marker	tendon of biceps brachii, granulocyte, gingival epithelium
AMELX	35	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, paraflocculus, frontal pole
KLK4	160	tissue_specific	yes	prostate gland, lower esophagus mucosa, kidney epithelium
MMP20	56		marker	left testis, testis, right testis

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KLK4	1,632
SLC24A4	1,456
WDR72	1,126
GPR68	923
AMELX	757
MMP20	503
ODAPH	341

Intra-cohort edges

A	B	Sources
AMELX	KLK4	string_interaction
AMELX	MMP20	string_interaction
AMELX	ODAPH	string_interaction
AMELX	WDR72	string_interaction
GPR68	ODAPH	string_interaction
GPR68	SLC24A4	string_interaction
GPR68	WDR72	string_interaction
KLK4	MMP20	string_interaction
KLK4	ODAPH	string_interaction
KLK4	WDR72	string_interaction
MMP20	ODAPH	string_interaction
MMP20	WDR72	string_interaction
ODAPH	SLC24A4	string_interaction
ODAPH	WDR72	string_interaction
SLC24A4	WDR72	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KLK4	Q9Y5K2	18
GPR68	Q15743	5
MMP20	O60882	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC24A4	Q8NFF2	70.84
WDR72	Q3MJ13	67.22
ODAPH	Q17RF5	61.64
AMELX	Q99217	59.51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 7 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC24A4 causes hypomineralized amelogenesis imperfecta (AI)	1	2855.0×	0.007	SLC24A4
Sodium/Calcium exchangers	1	259.6×	0.037	SLC24A4
Collagen formation	1	114.2×	0.055	MMP20
SLC transporter disorders	1	51.0×	0.071	SLC24A4
Assembly of collagen fibrils and other multimeric structures	1	50.1×	0.071	MMP20
Collagen degradation	1	43.9×	0.071	MMP20
Disorders of transmembrane transporters	1	34.8×	0.071	SLC24A4
R-HSA-425393	1	32.4×	0.071	SLC24A4
Degradation of the extracellular matrix	1	29.4×	0.071	MMP20
Post-translational protein phosphorylation	1	25.0×	0.075	AMELX
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	21.6×	0.078	AMELX
Class A/1 (Rhodopsin-like receptors)	1	18.5×	0.084	GPR68
Extracellular matrix organization	1	15.8×	0.086	MMP20
SLC-mediated transmembrane transport	1	14.8×	0.086	SLC24A4
G alpha (q) signalling events	1	14.3×	0.086	GPR68
Transport of small molecules	1	6.3×	0.178	SLC24A4
Post-translational protein modification	1	4.8×	0.215	AMELX
Disease	1	3.3×	0.286	SLC24A4
Metabolism of proteins	1	3.1×	0.286	AMELX

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
amelogenesis	4	802.5×	3e-10	SLC24A4, AMELX, KLK4, MMP20
biomineral tissue development	3	277.8×	4e-06	WDR72, AMELX, KLK4
enamel mineralization	2	343.9×	3e-04	SLC24A4, AMELX
extracellular matrix disassembly	2	104.7×	0.002	KLK4, MMP20
cone photoresponse recovery	1	1203.7×	0.006	SLC24A4
regulation of eating behavior	1	1203.7×	0.006	SLC24A4
response to high light intensity	1	802.5×	0.006	SLC24A4
olfactory nerve maturation	1	802.5×	0.006	SLC24A4
tooth mineralization	1	802.5×	0.006	AMELX
positive regulation of tooth mineralization	1	802.5×	0.006	AMELX
regulation of enamel mineralization	1	802.5×	0.006	MMP20
cellular response to high light intensity	1	802.5×	0.006	SLC24A4
response to melanocyte-stimulating hormone	1	802.5×	0.006	SLC24A4
positive regulation of osteoclast development	1	601.9×	0.007	GPR68
positive regulation of enamel mineralization	1	481.5×	0.009	ODAPH
positive regulation of biomineral tissue development	1	401.2×	0.009	ODAPH
calcium ion export across plasma membrane	1	401.2×	0.009	SLC24A4
response to odorant	1	401.2×	0.009	SLC24A4
negative regulation of monocyte differentiation	1	343.9×	0.009	GPR68
osteoclast development	1	300.9×	0.009	GPR68
negative regulation of calcium-mediated signaling	1	300.9×	0.009	SLC24A4
cellular response to pH	1	300.9×	0.009	GPR68
response to fluid shear stress	1	267.5×	0.010	GPR68
membrane repolarization	1	185.2×	0.014	SLC24A4
drinking behavior	1	141.6×	0.017	SLC24A4
monocyte differentiation	1	114.6×	0.021	GPR68
cellular response to acidic pH	1	104.7×	0.022	GPR68
positive regulation of collagen biosynthetic process	1	92.6×	0.024	AMELX
calcium ion import across plasma membrane	1	77.7×	0.027	SLC24A4
phototransduction	1	70.8×	0.029	SLC24A4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 6

Druggability breadth: 4 of 7 evidence-associated genes (57%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MMP20	1	3
SLC24A4	0	0
ODAPH	0	0
WDR72	0	0
GPR68	0	0
AMELX	0	0
KLK4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MARIMASTAT	3	MMP20

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GPR68	21	Functional:12, Binding:9
KLK4	13	Binding:13
MMP20	4	Binding:4
SLC24A4	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KLK4	3.4.21.B12
MMP20	3.4.24.B6

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MARIMASTAT	3	MMP20

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	MMP20
C	Druggable family + PDB, no drug	2	GPR68, KLK4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	SLC24A4, ODAPH, WDR72, AMELX

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ODAPH	0	MMP20
WDR72	0	MMP20
KLK4	13	MMP20
SLC24A4	1	—
GPR68	21	—
AMELX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.