amelogenesis imperfecta hypomaturation type 2A5

Summary

amelogenesis imperfecta hypomaturation type 2A5 (MONDO:0014385) is a disease caused by SLC24A4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SLC24A4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amelogenesis imperfecta hypomaturation type 2A5
Mondo ID	MONDO:0014385
OMIM	615887
DOID	DOID:0110063
UMLS	C4014578
MedGen	863015
GARD	0016028
Is cancer (heuristic)	no

Also known as: AI2A5 · amelogenesis imperfecta caused by mutation in SLC24A4 · amelogenesis imperfecta, hypomaturation type, IIA5 · amelogenesis imperfecta, type IIA5 · SLC24A4 amelogenesis imperfecta

Data availability: 5 ClinVar variants · 4 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 hypomaturation type 2A5

Related subtypes (6): 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, 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

5 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
139657	NM_153646.4(SLC24A4):c.1015C>T (p.Arg339Ter)	SLC24A4	Pathogenic	no assertion criteria provided
139658	NM_153646.4(SLC24A4):c.1495A>T (p.Ser499Cys)	SLC24A4	Pathogenic	no assertion criteria provided
139659	NM_153646.4(SLC24A4):c.437C>T (p.Ala146Val)	SLC24A4	Pathogenic	no assertion criteria provided
689492	NM_153646.4(SLC24A4):c.1192C>T (p.Gln398Ter)	SLC24A4	Pathogenic	no assertion criteria provided
2445420	NM_153646.4(SLC24A4):c.1716+5G>A	SLC24A4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
SLC24A4	Strong	Autosomal recessive	amelogenesis imperfecta hypomaturation type 2A5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC24A4	Orphanet:100032	Hypocalcified amelogenesis imperfecta
SLC24A4	Orphanet:100033	Hypomaturation amelogenesis imperfecta

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC24A4	HGNC:10978	ENSG00000140090	Q8NFF2	Sodium/potassium/calcium exchanger 4	gencc,clinvar

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(+).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

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

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
primary visual cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC24A4	168	broad	marker	monocyte, leukocyte, primary visual cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC24A4	1,456

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC24A4	Q8NFF2	70.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 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 1 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	11420.0×	7e-04	SLC24A4
Sodium/Calcium exchangers	1	1038.2×	0.004	SLC24A4
SLC transporter disorders	1	203.9×	0.012	SLC24A4
Disorders of transmembrane transporters	1	139.3×	0.012	SLC24A4
R-HSA-425393	1	129.8×	0.012	SLC24A4
SLC-mediated transmembrane transport	1	59.2×	0.023	SLC24A4
Transport of small molecules	1	25.1×	0.045	SLC24A4
Disease	1	13.1×	0.076	SLC24A4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cone photoresponse recovery	1	8426.0×	7e-04	SLC24A4
regulation of eating behavior	1	8426.0×	7e-04	SLC24A4
response to high light intensity	1	5617.3×	7e-04	SLC24A4
olfactory nerve maturation	1	5617.3×	7e-04	SLC24A4
cellular response to high light intensity	1	5617.3×	7e-04	SLC24A4
response to melanocyte-stimulating hormone	1	5617.3×	7e-04	SLC24A4
calcium ion export across plasma membrane	1	2808.7×	0.001	SLC24A4
response to odorant	1	2808.7×	0.001	SLC24A4
negative regulation of calcium-mediated signaling	1	2106.5×	0.001	SLC24A4
amelogenesis	1	1404.3×	0.002	SLC24A4
membrane repolarization	1	1296.3×	0.002	SLC24A4
enamel mineralization	1	1203.7×	0.002	SLC24A4
drinking behavior	1	991.3×	0.002	SLC24A4
calcium ion import across plasma membrane	1	543.6×	0.003	SLC24A4
phototransduction	1	495.6×	0.003	SLC24A4
calcium ion homeostasis	1	443.5×	0.004	SLC24A4
regulation of G protein-coupled receptor signaling pathway	1	374.5×	0.004	SLC24A4
calcium ion transmembrane transport	1	210.7×	0.006	SLC24A4
sodium ion transmembrane transport	1	203.0×	0.006	SLC24A4
monoatomic ion transport	1	156.0×	0.008	SLC24A4
sensory perception of smell	1	156.0×	0.008	SLC24A4
intracellular calcium ion homeostasis	1	145.3×	0.008	SLC24A4
potassium ion transmembrane transport	1	135.9×	0.008	SLC24A4
detection of chemical stimulus involved in sensory perception of smell	1	123.9×	0.008	SLC24A4
positive regulation of gene expression	1	38.7×	0.026	SLC24A4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC24A4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC24A4	1	Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	SLC24A4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC24A4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.