amelogenesis imperfecta, type 3A

Summary

amelogenesis imperfecta, type 3A (MONDO:0007538) is a disease caused by SACK1H (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: SACK1H (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amelogenesis imperfecta, type 3A
Mondo ID	MONDO:0007538
MeSH	C562880
OMIM	130900
DOID	DOID:0110055
SNOMED CT	109471001
UMLS	C5886770
MedGen	1854533
GARD	0024562
Is cancer (heuristic)	no

Also known as: ADHCAI · AI3 · AI3A · amelogenesis imperfecta caused by mutation in FAM83H · amelogenesis imperfecta hypomineralization type · amelogenesis imperfecta type 3 · amelogenesis imperfecta type III · amelogenesis imperfecta, type 3A · amelogenesis imperfecta, type III · FAM83H amelogenesis imperfecta

Data availability: 18 ClinVar variants · 6 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 › hypocalcified amelogenesis imperfecta › amelogenesis imperfecta, type 3A

Related subtypes (2): amelogenesis imperfecta type 3B, amelogenesis imperfecta, type 3C

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:

13 pathogenic, 3 uncertain significance, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30930	NM_198488.5(SACK1H):c.1366C>T (p.Gln456Ter)	SACK1H	Pathogenic	no assertion criteria provided
4819085	NM_198488.5(SACK1H):c.1403_1413del (p.Arg468fs)	SACK1H	Pathogenic	criteria provided, single submitter
770	NM_198488.5(SACK1H):c.973C>T (p.Arg325Ter)	SACK1H	Pathogenic	criteria provided, single submitter
771	NM_198488.5(SACK1H):c.1192C>T (p.Gln398Ter)	SACK1H	Pathogenic	no assertion criteria provided
772	NM_198488.5(SACK1H):c.1243G>T (p.Glu415Ter)	SACK1H	Pathogenic	no assertion criteria provided
773	NM_198488.5(SACK1H):c.891T>A (p.Tyr297Ter)	SACK1H	Pathogenic	no assertion criteria provided
774	NM_198488.5(SACK1H):c.1380G>A (p.Trp460Ter)	SACK1H	Pathogenic	no assertion criteria provided
775	NM_198488.5(SACK1H):c.2029C>T (p.Gln677Ter)	SACK1H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
776	NM_198488.5(SACK1H):c.1408C>T (p.Gln470Ter)	SACK1H	Pathogenic	no assertion criteria provided
777	NM_198488.5(SACK1H):c.860C>A (p.Ser287Ter)	SACK1H	Pathogenic	no assertion criteria provided
778	NM_198488.5(SACK1H):c.2080G>T (p.Glu694Ter)	SACK1H	Pathogenic	no assertion criteria provided
779	NM_198488.5(SACK1H):c.1872_1873del (p.Leu625fs)	SACK1H	Pathogenic	no assertion criteria provided
780	NM_198488.5(SACK1H):c.923_924del (p.Leu308fs)	SACK1H	Pathogenic	no assertion criteria provided
781	NM_198488.5(SACK1H):c.1379G>A (p.Trp460Ter)	SACK1H	Pathogenic	no assertion criteria provided
402847	NM_198488.5(SACK1H):c.601C>T (p.Gln201Ter)	SACK1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779457	NM_212557.4(AMTN):c.512G>A (p.Arg171His)	AMTN	Uncertain significance	criteria provided, single submitter
3891716	NM_198488.5(SACK1H):c.1096G>C (p.Ala366Pro)	SACK1H	Uncertain significance	criteria provided, multiple submitters, no conflicts
689699	NM_198488.5(SACK1H):c.682G>A (p.Val228Ile)	SACK1H	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 7 · 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
ITGB6	Strong	Autosomal recessive	amelogenesis imperfecta type 1H	4
SACK1H	Strong	Autosomal dominant	amelogenesis imperfecta, type 3A	3
SLC24A4	Strong	Autosomal recessive	amelogenesis imperfecta hypomaturation type 2A5	6
AMTN	Supportive	Autosomal dominant	amelogenesis imperfecta, type 3A	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SACK1H	Orphanet:100032	Hypocalcified amelogenesis imperfecta
AMTN	Orphanet:100032	Hypocalcified amelogenesis imperfecta
SLC24A4	Orphanet:100032	Hypocalcified amelogenesis imperfecta
SLC24A4	Orphanet:100033	Hypomaturation amelogenesis imperfecta
ITGB6	Orphanet:100031	Hypoplastic amelogenesis imperfecta
ITGB6	Orphanet:100032	Hypocalcified amelogenesis imperfecta
ITGB6	Orphanet:2850	Alopecia-intellectual disability syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SACK1H	HGNC:24797	ENSG00000180921	Q6ZRV2	Protein FAM83H	gencc,clinvar
AMTN	HGNC:33188	ENSG00000187689	Q6UX39	Amelotin	gencc,clinvar
SLC24A4	HGNC:10978	ENSG00000140090	Q8NFF2	Sodium/potassium/calcium exchanger 4	gencc
ITGB6	HGNC:6161	ENSG00000115221	P18564	Integrin beta-6	gencc

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.
AMTN	Amelotin	Is a promoter of calcium phosphate mineralization, playing a critical role in the formation of the compact, mineralized, aprismatic enamel surface layer during the maturation stage of amelogenesis.
SLC24A4	Sodium/potassium/calcium exchanger 4	Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+).
ITGB6	Integrin beta-6	Integrin alpha-V:beta-6 (ITGAV:ITGB6) is a receptor for fibronectin and cytotactin.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SACK1H	Other/Unknown	no		SACK1, PLDc_FAM83H_N, FAM83
AMTN	Other/Unknown	no		Amelotin
SLC24A4	Other/Unknown	no		K/Na/Ca-exchanger, NaCa_Exmemb, NCX_ion-bd_dom_sf
ITGB6	Other/Unknown	no		Integrin_bsu_VWA, Integrin_bsu_tail, EGF_extracell

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
esophagus mucosa	1
lower esophagus mucosa	1
right uterine tube	1
minor salivary gland	1
saliva-secreting gland	1
tonsil	1
leukocyte	1
monocyte	1
primary visual cortex	1
biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
visceral pleura	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
AMTN	38	tissue_specific	marker	tonsil, minor salivary gland, saliva-secreting gland
SLC24A4	168	broad	marker	monocyte, leukocyte, primary visual cortex
ITGB6	188	broad	marker	visceral pleura, biceps brachii, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ITGB6	1,461
SLC24A4	1,456
SACK1H	1,214
AMTN	497

Intra-cohort edges

A	B	Sources
AMTN	SACK1H	string_interaction
SACK1H	SLC24A4	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · 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
SLC24A4	Q8NFF2	70.84
SACK1H	Q6ZRV2	50.43
AMTN	Q6UX39	48.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 4 evidence-associated genes (3 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 3 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	3806.7×	0.006	SLC24A4
Sodium/Calcium exchangers	1	346.1×	0.030	SLC24A4
Elastic fibre formation	1	112.0×	0.041	ITGB6
TGF-beta receptor signaling activates SMADs	1	108.8×	0.041	ITGB6
Molecules associated with elastic fibres	1	102.9×	0.041	ITGB6
SLC transporter disorders	1	68.0×	0.044	SLC24A4
Signaling by TGF-beta Receptor Complex	1	66.8×	0.044	ITGB6
ECM proteoglycans	1	50.1×	0.044	ITGB6
Disorders of transmembrane transporters	1	46.4×	0.044	SLC24A4
Integrin cell surface interactions	1	44.8×	0.044	ITGB6
R-HSA-425393	1	43.3×	0.044	SLC24A4
Signaling by TGFB family members	1	38.5×	0.045	ITGB6
Post-translational protein phosphorylation	1	33.4×	0.048	AMTN
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	28.8×	0.051	AMTN
Extracellular matrix organization	1	21.0×	0.065	ITGB6
SLC-mediated transmembrane transport	1	19.7×	0.065	SLC24A4
Transport of small molecules	1	8.4×	0.142	SLC24A4
Post-translational protein modification	1	6.4×	0.173	AMTN
Disease	1	4.4×	0.235	SLC24A4
Metabolism of proteins	1	4.1×	0.235	AMTN
Signal Transduction	1	3.4×	0.267	ITGB6

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
amelogenesis	2	702.2×	1e-04	SLC24A4, ITGB6
enamel mineralization	2	601.9×	1e-04	SLC24A4, ITGB6
biomineral tissue development	2	324.1×	3e-04	SACK1H, AMTN
cone photoresponse recovery	1	2106.5×	0.003	SLC24A4
protein localization to cytoskeleton	1	2106.5×	0.003	SACK1H
transforming growth factor beta production	1	2106.5×	0.003	ITGB6
regulation of eating behavior	1	2106.5×	0.003	SLC24A4
response to high light intensity	1	1404.3×	0.003	SLC24A4
olfactory nerve maturation	1	1404.3×	0.003	SLC24A4
memory T cell differentiation	1	1404.3×	0.003	ITGB6
cellular response to high light intensity	1	1404.3×	0.003	SLC24A4
response to melanocyte-stimulating hormone	1	1404.3×	0.003	SLC24A4
Langerhans cell differentiation	1	1053.2×	0.004	ITGB6
bronchiole development	1	842.6×	0.004	ITGB6
positive regulation of enamel mineralization	1	842.6×	0.004	AMTN
positive regulation of biomineral tissue development	1	702.2×	0.004	AMTN
calcium ion export across plasma membrane	1	702.2×	0.004	SLC24A4
response to odorant	1	702.2×	0.004	SLC24A4
negative regulation of calcium-mediated signaling	1	526.6×	0.005	SLC24A4
hard palate development	1	421.3×	0.007	ITGB6
membrane repolarization	1	324.1×	0.008	SLC24A4
drinking behavior	1	247.8×	0.009	SLC24A4
phospholipid homeostasis	1	247.8×	0.009	ITGB6
intermediate filament cytoskeleton organization	1	234.1×	0.009	SACK1H
cell adhesion	2	18.7×	0.009	AMTN, ITGB6
surfactant homeostasis	1	200.6×	0.011	ITGB6
cell adhesion mediated by integrin	1	168.5×	0.012	ITGB6
calcium ion import across plasma membrane	1	135.9×	0.014	SLC24A4
phototransduction	1	123.9×	0.015	SLC24A4
skin development	1	110.9×	0.016	ITGB6

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
SACK1H	0	0
AMTN	0	0
SLC24A4	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
SLC24A4	1	Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	0
E	Difficult family or no structure, no drug	3	SACK1H, AMTN, SLC24A4

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	—
AMTN	0	—
SLC24A4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.