X-linked amelogenesis imperfecta hypoplastic/hypomaturation 2

Summary

X-linked amelogenesis imperfecta hypoplastic/hypomaturation 2 (MONDO:0010522) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked amelogenesis imperfecta hypoplastic/hypomaturation 2
Mondo ID	MONDO:0010522
OMIM	301201
DOID	DOID:0110059
UMLS	C1845051
MedGen	336845
GARD	0009944
Is cancer (heuristic)	no

Also known as: AIH3 (formerly) · amelogenesis imperfecta 3, hypoplastic type · amelogenesis imperfecta 3, hypoplastic type (formerly) · amelogenesis imperfecta 3, hypoplastic type, formerly · amelogenesis imperfecta, hypoplastic/hypomaturation, X-linked type 2 · amelogenesis imperfecta, type IE, X-linked 2 · X-linked amelogenesis imperfecta hypoplastic/hypomaturation type 2

Data availability: 6 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › amelogenesis imperfecta › X-linked amelogenesis imperfecta hypoplastic/hypomaturation 2

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

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

6 retrieved; paginated sample, class counts are floors:

6 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
96976	NM_001142.2(AMELX):c.129G>C (p.Gln43His)	AMELX	not provided	no classification provided
96977	NM_001142.2(AMELX):c.131G>A (p.Ser44Asn)	AMELX	not provided	no classification provided
96978	NM_001142.2(AMELX):c.132C>A (p.Ser44Arg)	ARHGAP6	not provided	no classification provided
96979	NM_198488.5(SACK1H):c.2250C>T (p.Gly750=)	SACK1H	not provided	no classification provided
96980	NM_198488.5(SACK1H):c.2765G>T (p.Arg922Leu)	SACK1H	not provided	no classification provided
96981	NM_198488.5(SACK1H):c.2766C>T (p.Arg922=)	SACK1H	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SACK1H	Orphanet:100032	Hypocalcified amelogenesis imperfecta
AMELX	Orphanet:100033	Hypomaturation amelogenesis imperfecta

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
SACK1H	HGNC:24797	ENSG00000180921	Q6ZRV2	Protein FAM83H	clinvar
AMELX	HGNC:461	ENSG00000125363	Q99217	Amelogenin, X isoform	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)
SACK1H	Protein FAM83H	May play a major role in the structural organization and calcification of developing enamel.
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: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SACK1H	Other/Unknown	no		SACK1, PLDc_FAM83H_N, FAM83
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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
esophagus mucosa	1
lower esophagus mucosa	1
right uterine tube	1
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
SACK1H	128	ubiquitous	yes	lower esophagus mucosa, esophagus mucosa, right uterine tube
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: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SACK1H	1,214
ARHGAP6	1,177
AMELX	757

Intra-cohort edges

A	B	Sources
AMELX	ARHGAP6	string_interaction
AMELX	SACK1H	string_interaction

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AMELX	Q99217	59.51
ARHGAP6	O43182	56.60
SACK1H	Q6ZRV2	50.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
biomineral tissue development	2	432.1×	2e-04	SACK1H, AMELX
protein localization to cytoskeleton	1	2808.7×	0.004	SACK1H
tooth mineralization	1	1872.4×	0.004	AMELX
positive regulation of tooth mineralization	1	1872.4×	0.004	AMELX
positive regulation of phospholipase C/protein kinase C signal transduction	1	1123.5×	0.005	ARHGAP6
amelogenesis	1	468.1×	0.010	AMELX
enamel mineralization	1	401.2×	0.010	AMELX
intermediate filament cytoskeleton organization	1	312.1×	0.011	SACK1H
negative regulation of focal adhesion assembly	1	255.3×	0.012	ARHGAP6
positive regulation of collagen biosynthetic process	1	216.1×	0.012	AMELX
positive regulation of intracellular signal transduction	1	216.1×	0.012	ARHGAP6
negative regulation of stress fiber assembly	1	193.7×	0.012	ARHGAP6
focal adhesion assembly	1	175.5×	0.012	ARHGAP6
actin filament polymerization	1	160.5×	0.012	ARHGAP6
response to calcium ion	1	106.0×	0.015	AMELX
epithelial to mesenchymal transition	1	104.0×	0.015	AMELX
chondrocyte differentiation	1	100.3×	0.015	AMELX
odontogenesis of dentin-containing tooth	1	100.3×	0.015	AMELX
response to nutrient	1	98.5×	0.015	AMELX
signal transduction	2	10.7×	0.016	SACK1H, AMELX
Rho protein signal transduction	1	82.6×	0.016	ARHGAP6
regulation of small GTPase mediated signal transduction	1	48.0×	0.026	ARHGAP6
osteoblast differentiation	1	40.4×	0.029	AMELX
actin filament organization	1	39.6×	0.029	ARHGAP6
regulation of cell population proliferation	1	38.5×	0.029	AMELX
response to xenobiotic stimulus	1	23.0×	0.046	AMELX
positive regulation of cell migration	1	20.6×	0.050	SACK1H
cell adhesion	1	12.5×	0.078	AMELX

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
SACK1H	0	0
AMELX	0	0
ARHGAP6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SACK1H, AMELX, ARHGAP6

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)
SACK1H	0	—
AMELX	0	—
ARHGAP6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.