amelogenesis imperfecta type 1E

Summary

amelogenesis imperfecta type 1E (MONDO:0010521) is a disease caused by AMELX (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: AMELX (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amelogenesis imperfecta type 1E
Mondo ID	MONDO:0010521
OMIM	301200
DOID	DOID:0110058
UMLS	C1845053
MedGen	336847
GARD	0009943
Is cancer (heuristic)	no

Also known as: AI1E · AIH1 · amelogenesis imperfecta caused by mutation in AMELX · amelogenesis imperfecta hypoplastic/hypomaturation X-linked 1 · amelogenesis imperfecta X-linked 1 · amelogenesis imperfecta, type 1E, X-linked dominant · amelogenesis imperfecta, type IE · AMELX amelogenesis imperfecta · enamel hypoplasia X-linked

Data availability: 18 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › amelogenesis imperfecta › amelogenesis imperfecta type 2 › amelogenesis imperfecta type 1E

Related subtypes (6): amelogenesis imperfecta type 2A1, 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

ClinVar germline variants

18 retrieved; paginated sample, class counts are floors:

11 pathogenic, 5 likely pathogenic, 1 uncertain significance, 1 vus-mid

ClinVar	Variant (HGVS)	Gene	Classification	Review
11136	NC_000023.11:g.(11295935_11295938)_(11300658_11300661)del	AMELX	Pathogenic	no assertion criteria provided
11138	NM_001142.2(AMELX):c.14_22del (p.Ile5_Ala8delinsThr)	AMELX	Pathogenic	no assertion criteria provided
11140	NM_001142.2(AMELX):c.110C>T (p.Thr37Ile)	AMELX	Pathogenic	no assertion criteria provided
11141	NM_001142.2(AMELX):c.529G>T (p.Glu177Ter)	AMELX	Pathogenic	no assertion criteria provided
11142	NM_001142.2(AMELX):c.166C>A (p.Pro56Thr)	AMELX	Pathogenic	criteria provided, single submitter
11144	NM_001142.2(AMELX):c.378del (p.Tyr127fs)	AMELX	Pathogenic	no assertion criteria provided
11146	NM_001142.2(AMELX):c.11G>C (p.Trp4Ser)	AMELX	Pathogenic	no assertion criteria provided
11137	NM_001142.2(AMELX):c.113del (p.Pro38fs)	ARHGAP6	Pathogenic	no assertion criteria provided
11143	NM_001142.2(AMELX):c.499del (p.Leu167fs)	ARHGAP6	Pathogenic	no assertion criteria provided
11145	NM_001142.2(AMELX):c.2T>C (p.Met1Thr)	ARHGAP6	Pathogenic	no assertion criteria provided
3256889	NM_001142.2(AMELX):c.167C>T (p.Pro56Leu)	ARHGAP6	Pathogenic	criteria provided, single submitter
3376363	NM_001142.2(AMELX):c.144+1G>A	AMELX	Likely pathogenic	criteria provided, single submitter
11139	NM_001142.2(AMELX):c.431del (p.Pro144fs)	ARHGAP6	Likely pathogenic	criteria provided, single submitter
1323884	NM_001142.2(AMELX):c.289C>T (p.Gln97Ter)	ARHGAP6	Likely pathogenic	criteria provided, single submitter
2445234	NM_001142.2(AMELX):c.47C>A (p.Ala16Asp)	ARHGAP6	Likely pathogenic	criteria provided, single submitter
3598004	NM_001142.2(AMELX):c.3G>A (p.Met1Ile)	ARHGAP6	Likely pathogenic	criteria provided, single submitter
2362820	NM_001142.2(AMELX):c.103-111A>G	AMELX	Uncertain significance	criteria provided, multiple submitters, no conflicts
4813875	NM_001142.2(AMELX):c.404A>C (p.Gln135Pro)	ARHGAP6	VUS-mid	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AMELX	Orphanet:100033	Hypomaturation amelogenesis imperfecta

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AMELX	HGNC:461	ENSG00000125363	Q99217	Amelogenin, X isoform	gencc,clinvar
ARHGAP6	HGNC:676	ENSG00000047648	O43182	Rho GTPase-activating protein 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AMELX	Amelogenin, X isoform	Plays a role in biomineralization.
ARHGAP6	Rho GTPase-activating protein 6	GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AMELX	Other/Unknown	no		Amelogenin
ARHGAP6	Other/Unknown	no		RhoGAP_dom, Rho_GTPase_activation_prot, RHOGAP6/36

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
frontal pole	1
male germ line stem cell (sensu Vertebrata) in testis	1
paraflocculus	1
cauda epididymis	1
choroid plexus epithelium	1
seminal vesicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AMELX	35	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, paraflocculus, frontal pole
ARHGAP6	267	ubiquitous	marker	seminal vesicle, cauda epididymis, choroid plexus epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARHGAP6	1,177
AMELX	757

Intra-cohort edges

A	B	Sources
AMELX	ARHGAP6	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AMELX	Q99217	59.51
ARHGAP6	O43182	56.60

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
RAC3 GTPase cycle	1	59.5×	0.040	ARHGAP6
Post-translational protein phosphorylation	1	50.1×	0.040	AMELX
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.040	AMELX
RHOA GTPase cycle	1	37.3×	0.040	ARHGAP6
Post-translational protein modification	1	9.6×	0.122	AMELX
Metabolism of proteins	1	6.2×	0.155	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tooth mineralization	1	2808.7×	0.004	AMELX
positive regulation of tooth mineralization	1	2808.7×	0.004	AMELX
positive regulation of phospholipase C/protein kinase C signal transduction	1	1685.2×	0.005	ARHGAP6
amelogenesis	1	702.2×	0.008	AMELX
enamel mineralization	1	601.9×	0.008	AMELX
negative regulation of focal adhesion assembly	1	383.0×	0.009	ARHGAP6
biomineral tissue development	1	324.1×	0.009	AMELX
positive regulation of collagen biosynthetic process	1	324.1×	0.009	AMELX
positive regulation of intracellular signal transduction	1	324.1×	0.009	ARHGAP6
negative regulation of stress fiber assembly	1	290.6×	0.009	ARHGAP6
focal adhesion assembly	1	263.3×	0.009	ARHGAP6
actin filament polymerization	1	240.7×	0.009	ARHGAP6
response to calcium ion	1	159.0×	0.010	AMELX
epithelial to mesenchymal transition	1	156.0×	0.010	AMELX
chondrocyte differentiation	1	150.5×	0.010	AMELX
odontogenesis of dentin-containing tooth	1	150.5×	0.010	AMELX
response to nutrient	1	147.8×	0.010	AMELX
Rho protein signal transduction	1	123.9×	0.011	ARHGAP6
regulation of small GTPase mediated signal transduction	1	72.0×	0.018	ARHGAP6
osteoblast differentiation	1	60.6×	0.020	AMELX
actin filament organization	1	59.3×	0.020	ARHGAP6
regulation of cell population proliferation	1	57.7×	0.020	AMELX
response to xenobiotic stimulus	1	34.5×	0.031	AMELX
cell adhesion	1	18.7×	0.055	AMELX
signal transduction	1	8.0×	0.121	AMELX

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AMELX	0	0
ARHGAP6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
E	Difficult family or no structure, no drug	2	AMELX, ARHGAP6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AMELX	0	—
ARHGAP6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.