SLC24A4

Summary

SLC24A4 (solute carrier family 24 member 4, HGNC:10978) is a protein-coding gene on chromosome 14q32.12, encoding Sodium/potassium/calcium exchanger 4 (Q8NFF2). Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+).

This gene encodes a sodium/potassium/calcium exchange protein. The encoded antiporter transports one calcium and one potassium ion in exchange for four sodium ions and has been implicated in amelogenesis and enamel maturation. Certain variants in this gene have been associated with skin, hair, and eye pigmentation, while other variants have been identified in people with hypomaturation-type amelogenesis imperfecta.

Source: NCBI Gene 123041 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amelogenesis imperfecta hypomaturation type 2A5 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 38
• Clinical variants (ClinVar): 186 total — 5 pathogenic
• Phenotypes (HPO): 7
• Druggable target: yes
• MANE Select transcript: NM_153646

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10978
Approved symbol	SLC24A4
Name	solute carrier family 24 member 4
Location	14q32.12
Locus type	gene with protein product
Status	Approved
Aliases	NCKX4
Ensembl gene	ENSG00000140090
Ensembl biotype	protein_coding
OMIM	609840
Entrez	123041

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000393265, ENST00000525557, ENST00000526482, ENST00000531433, ENST00000532405, ENST00000554461, ENST00000554925, ENST00000556739, ENST00000676001

RefSeq mRNA: 5 — MANE Select: NM_153646 NM_001378620, NM_001425254, NM_153646, NM_153647, NM_153648

CCDS: CCDS45155, CCDS45156, CCDS9903

Canonical transcript exons

ENST00000532405 — 17 exons

Exon	Start	End
ENSE00001704568	92442089	92442173
ENSE00001758281	92443400	92443474
ENSE00001791793	92442713	92442816
ENSE00002191205	92323165	92323960
ENSE00003489845	92445317	92445342
ENSE00003501117	92439335	92439409
ENSE00003506793	92486666	92486780
ENSE00003564475	92453900	92454069
ENSE00003570997	92325868	92325978
ENSE00003601716	92492175	92492240
ENSE00003620417	92433912	92433988
ENSE00003624578	92449074	92449216
ENSE00003632040	92491665	92491777
ENSE00003662483	92482680	92482846
ENSE00003670862	92447371	92447424
ENSE00003682560	92456404	92456608
ENSE00003746464	92493476	92501481

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 89.47.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3040 / max 86.3141, expressed in 219 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141085	1.2744	218
141084	0.0296	17

Top tissues by expression

243 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	89.47	gold quality
leukocyte	CL:0000738	88.87	gold quality
primary visual cortex	UBERON:0002436	83.73	gold quality
middle temporal gyrus	UBERON:0002771	83.23	gold quality
sural nerve	UBERON:0015488	83.02	gold quality
Brodmann (1909) area 23	UBERON:0013554	82.60	gold quality
blood	UBERON:0000178	81.63	gold quality
granulocyte	CL:0000094	81.45	gold quality
endothelial cell	CL:0000115	79.90	silver quality
occipital lobe	UBERON:0002021	79.53	gold quality
buccal mucosa cell	CL:0002336	78.81	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.49	gold quality
pons	UBERON:0000988	77.18	gold quality
medial globus pallidus	UBERON:0002477	76.92	gold quality
globus pallidus	UBERON:0001875	75.98	gold quality
tibial nerve	UBERON:0001323	74.60	gold quality
postcentral gyrus	UBERON:0002581	74.33	gold quality
superior frontal gyrus	UBERON:0002661	73.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.80	gold quality
right frontal lobe	UBERON:0002810	73.61	gold quality
prefrontal cortex	UBERON:0000451	73.28	gold quality
Brodmann (1909) area 9	UBERON:0013540	73.08	gold quality
corpus callosum	UBERON:0002336	73.06	gold quality
frontal cortex	UBERON:0001870	73.04	gold quality
substantia nigra pars compacta	UBERON:0001965	72.66	gold quality
medulla oblongata	UBERON:0001896	72.23	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	72.14	gold quality
midbrain	UBERON:0001891	72.02	gold quality
substantia nigra	UBERON:0002038	72.01	gold quality
parietal lobe	UBERON:0001872	71.89	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	64.75
E-GEOD-137537	yes	18.07
E-ANND-3	yes	4.64
E-GEOD-111727	no	212.80
E-CURD-11	no	6.46
E-MTAB-5061	no	2.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

283 targeting SLC24A4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-27A-3P	99.98	72.13	2955

Literature-anchored findings (GeneRIF, showing 13)

• identification and sequencing, as well as mapping to chromosomal region 14q32 (PMID:12379639)
• IRF4 and SLC24A4 loci are associated with human hair color and skin pigmentation. (PMID:18483556)
• Taken together, these data demonstrate a potentially important role for NCX1 in control of Ca2+ homeostasis and link store depletion via STIM1 directly with NCX activation. (PMID:21126331)
• These findings support a key role for SLC24A4 in calcium transport during enamel formation. (PMID:23375655)
• enamel maturation is dependent upon STIM1 and SLC24A4 function, and that there are important differences in the Ca(2+) transcellular transport systems used by secretory- and maturation-stage ameloblasts. (PMID:24621671)
• Brain DNA methylation in sLC24A4 was associated with pathological Alzheimer disease. (PMID:25365775)
• The expressions of NCX1 and NCKX4 were significantly higher in the patent ductus arteriosus group at both the protein and mRNA levels. (PMID:25500693)
• pigment cells express robust, functional NCKX4 activity (PMID:27093457)
• mutations in SLC24A4 and SLC24A5 are responsible for the phenotypic defects observed in human amylogenesis imperfecta and non-syndromic oculocutaneous albinism patients. (PMID:27129268)
• no significant relation was noted between SLC24A4 rs10498633 and late-onset Alzheimer;s disease risk in neither apolipoprotein E (APOE) epsilon4 carriers nor non-carriers after adjusting for age and gender (PMID:27215332)
• This nonsense sequence variant c.1192C > T (p.Gln398*) is the sixth disease-causing variant in SLC24A4, which extends its mutation spectrum and confirms the role of this gene in the morphogenesis of human tooth enamel. The identified variant highlights the critical role of SLC24A4 in causing a rare Amelogenesis imperfecta (AI) type in humans. (PMID:32380970)
• Association between brown eye colour in rs12913832:GG individuals and SNPs in TYR, TYRP1, and SLC24A4. (PMID:32915910)
• Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-exchanger isoform 4, NCKX4. (PMID:33199372)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc24a4a	ENSDARG00000015425
danio_rerio	slc24a4b	ENSDARG00000067509
mus_musculus	Slc24a4	ENSMUSG00000041771
rattus_norvegicus	Slc24a4	ENSRNOG00000006729
drosophila_melanogaster	CG17167	FBGN0039941
drosophila_melanogaster	CG12061	FBGN0040031
drosophila_melanogaster	zyd	FBGN0265767

Paralogs (4): SLC24A1 (ENSG00000074621), SLC24A2 (ENSG00000155886), SLC24A3 (ENSG00000185052), SLC24A5 (ENSG00000188467)

Protein

Protein identifiers

Sodium/potassium/calcium exchanger 4 — Q8NFF2 (reviewed: Q8NFF2)

Alternative names: Na(+)/K(+)/Ca(2+)-exchange protein 4, Solute carrier family 24 member 4

All UniProt accessions (3): Q8NFF2, G3V505, H0YCX3

UniProt curated annotations — full annotation on UniProt →

Function. Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+). Controls the rapid response termination and proper regulation of adaptation in olfactory sensory neurons (OSNs) which subsequently influences how odor information is encoded and perceived. May play a role in calcium transport during amelogenesis.

Subcellular location. Cell membrane. Cytoplasm.

Tissue specificity. Expressed abundantly in all regions of the brain, aorta, lung and thymus. Expressed at lower levels in the stomach and intestine.

Disease relevance. Amelogenesis imperfecta, hypomaturation type, 2A5 (AI2A5) [MIM:615887] A defect of enamel formation. The disorder involves both primary and secondary dentitions. The teeth have a shiny agar jelly appearance and the enamel is softer than normal. Brown pigment is present in middle layers of enamel. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variants in SLC24A4 define the skin/hair/eye pigmentation variation locus 6 (SHEP6) [MIM:210750]. Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair.

Similarity. Belongs to the Ca(2+):cation antiporter (CaCA) (TC 2.A.19) family. SLC24A subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8NFF2-1	1	yes
Q8NFF2-2	2
Q8NFF2-3	3
Q8NFF2-4	4

RefSeq proteins (5): NP_001365549, NP_001412183, NP_705932, NP_705933, NP_705934 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004481	K/Na/Ca-exchanger	Family
IPR004837	NaCa_Exmemb	Domain
IPR044880	NCX_ion-bd_dom_sf	Homologous_superfamily

Pfam: PF01699

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(out) + K(+)(out) + 4 Na(+)(in) = Ca(2+)(in) + K(+)(in) + 4 Na(+)(out) (RHEA:69967)

UniProt features (43 total): topological domain 11, transmembrane region 10, sequence variant 7, splice variant 4, repeat 2, compositionally biased region 2, glycosylation site 2, sequence conflict 2, signal peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFF2-F1	70.84	0.16

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (2): 69, 76

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-425561	Sodium/Calcium exchangers
R-HSA-5619055	Defective SLC24A4 causes hypomineralized amelogenesis imperfecta (AI)
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters

MSigDB gene sets: 263 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, YAATNRNNNYNATT_UNKNOWN, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_PHOTOTRANSDUCTION, TGACCTY_ERR1_Q2, LHX3_01

GO Biological Process (29): monoatomic ion transport (GO:0006811), intracellular calcium ion homeostasis (GO:0006874), phototransduction (GO:0007602), sensory perception of smell (GO:0007608), regulation of G protein-coupled receptor signaling pathway (GO:0008277), response to high light intensity (GO:0009644), positive regulation of gene expression (GO:0010628), olfactory nerve maturation (GO:0021630), sodium ion transmembrane transport (GO:0035725), cone photoresponse recovery (GO:0036368), drinking behavior (GO:0042756), negative regulation of calcium-mediated signaling (GO:0050849), detection of chemical stimulus involved in sensory perception of smell (GO:0050911), calcium ion homeostasis (GO:0055074), enamel mineralization (GO:0070166), calcium ion transmembrane transport (GO:0070588), cellular response to high light intensity (GO:0071486), potassium ion transmembrane transport (GO:0071805), membrane repolarization (GO:0086009), amelogenesis (GO:0097186), calcium ion import across plasma membrane (GO:0098703), regulation of eating behavior (GO:1903998), calcium ion export across plasma membrane (GO:1990034), response to melanocyte-stimulating hormone (GO:1990680), response to odorant (GO:1990834), potassium ion transport (GO:0006813), sodium ion transport (GO:0006814), calcium ion transport (GO:0006816), transmembrane transport (GO:0055085)

GO Molecular Function (6): calcium channel activity (GO:0005262), calmodulin binding (GO:0005516), calcium, potassium:sodium antiporter activity (GO:0008273), symporter activity (GO:0015293), calcium-dependent protein binding (GO:0048306), antiporter activity (GO:0015297)

GO Cellular Component (7): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), apical plasma membrane (GO:0016324), vesicle (GO:0031982), cone photoreceptor outer segment (GO:0120199), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Metal ion SLC transporters	1
SLC transporter disorders	1
Transport of small molecules	1
Disorders of transmembrane transporters	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic cation transmembrane transport	3
cellular anatomical structure	3
protein binding	2
secondary active transmembrane transporter activity	2
transport	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
signal transduction	1
detection of light stimulus	1
sensory perception of chemical stimulus	1
G protein-coupled receptor signaling pathway	1
regulation of signal transduction	1
response to light intensity	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
olfactory nerve development	1
cranial nerve maturation	1
sodium ion transport	1
response to light stimulus	1
feeding behavior	1
calcium-mediated signaling	1
regulation of calcium-mediated signaling	1
negative regulation of intracellular signal transduction	1
sensory perception of smell	1
detection of chemical stimulus involved in sensory perception	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
tooth mineralization	1
amelogenesis	1
calcium ion transport	1
response to high light intensity	1
cellular response to light intensity	1
potassium ion transport	1
regulation of membrane potential	1
odontogenesis of dentin-containing tooth	1
anatomical structure formation involved in morphogenesis	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
calcium:sodium antiporter activity	1

Protein interactions and networks

STRING

1439 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC24A4	TPCN2	Q8NHX9	914
SLC24A4	SLC45A2	Q9UMX9	854
SLC24A4	OCA2	Q04671	849
SLC24A4	ZCWPW1	Q9H0M4	827
SLC24A4	RIN3	Q8TB24	819
SLC24A4	NME8	Q8N427	785
SLC24A4	TYR	P14679	733
SLC24A4	MC1R	Q01726	731
SLC24A4	ASIP	P42127	723
SLC24A4	CASS4	Q9NQ75	720
SLC24A4	TYRP1	P17643	714
SLC24A4	ABCA7	Q8IZY2	706
SLC24A4	IRF4	Q15306	701
SLC24A4	ODAPH	Q17RF5	696
SLC24A4	FERMT2	Q96AC1	691

IntAct

2 interactions, top by confidence:

A	B	Type	Score
SLC24A4	MYL12B	psi-mi:“MI:0914”(association)	0.350

BioGRID (15): SLC24A4 (Affinity Capture-RNA), SLC24A4 (Affinity Capture-MS), SLC24A4 (Co-fractionation), SPON1 (Co-fractionation), VPS26A (Co-fractionation), ACTA2 (Affinity Capture-MS), ACTG1 (Affinity Capture-MS), CTSD (Affinity Capture-MS), GOLPH3 (Affinity Capture-MS), MYH10 (Affinity Capture-MS), MYL12B (Affinity Capture-MS), PUF60 (Affinity Capture-MS), TMOD3 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), TPM4 (Affinity Capture-MS)

ESM2 similar proteins: A0A096X8J7, A3QM97, A7T1N0, B2RXE2, E9Q3M5, G3X939, G5EBK1, M5A7P9, O13726, O80739, P19334, P26432, P26433, P31662, P32847, P34586, P48764, P48994, P79100, Q01345, Q04121, Q09573, Q14940, Q1ZXJ0, Q28362, Q69RI8, Q6A4L1, Q6AI14, Q6H4R6, Q6RI88, Q84MS3, Q8BJI1, Q8BTY2, Q8BUE1, Q8CFW1, Q8NFF2, Q8T5S1, Q8VIH3, Q93380, Q94225

Diamond homologs: B8K1V7, O22252, O54701, P23685, P32418, P48765, P48766, P48767, P48768, P57103, P70414, P70549, Q01728, Q2R041, Q6H641, Q8BUN9, Q8CGQ8, Q8K596, Q8NFF2, Q99PD7, Q9EPQ0, Q9HC58, Q9UI40, Q9UPR5, Q9VDG5, Q9VN12, S4R2P9, F1NXU8, O04034, O16242, P87122, Q49SH1, Q6AXS0, Q71RS6, Q925Q3, Q9FKP1, Q9FKP2, Q9U6A0, O60721, O46383

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SLC24A4	“down-regulates quantity”	calcium(2+)	relocalization
SLC24A4	“down-regulates quantity”	potassium(1+)	relocalization
SLC24A4	“up-regulates quantity”	sodium(1+)	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

186 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	0
Uncertain significance	98
Likely benign	27
Benign	41

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1326286	NM_153646.4(SLC24A4):c.613C>T (p.Arg205Ter)	Pathogenic
139657	NM_153646.4(SLC24A4):c.1015C>T (p.Arg339Ter)	Pathogenic
139658	NM_153646.4(SLC24A4):c.1495A>T (p.Ser499Cys)	Pathogenic
139659	NM_153646.4(SLC24A4):c.437C>T (p.Ala146Val)	Pathogenic
689492	NM_153646.4(SLC24A4):c.1192C>T (p.Gln398Ter)	Pathogenic

SpliceAI

3959 predictions. Top by Δscore:

Variant	Effect	Δscore
14:92325861:A:AG	acceptor_gain	1.0000
14:92433910:A:AG	acceptor_gain	1.0000
14:92433910:AGC:A	acceptor_gain	1.0000
14:92433911:G:GG	acceptor_gain	1.0000
14:92433911:GC:G	acceptor_gain	1.0000
14:92433911:GCG:G	acceptor_gain	1.0000
14:92433987:GT:G	donor_gain	1.0000
14:92442083:TTTCA:T	acceptor_loss	1.0000
14:92442087:A:AG	acceptor_gain	1.0000
14:92442087:AG:A	acceptor_loss	1.0000
14:92442088:G:A	acceptor_loss	1.0000
14:92442088:G:GG	acceptor_gain	1.0000
14:92442088:GA:G	acceptor_gain	1.0000
14:92442138:G:GT	donor_gain	1.0000
14:92442170:ATTGG:A	donor_loss	1.0000
14:92442171:TTGGT:T	donor_loss	1.0000
14:92442173:GGTAA:G	donor_loss	1.0000
14:92442174:G:GG	donor_gain	1.0000
14:92442174:G:T	donor_loss	1.0000
14:92442175:T:A	donor_loss	1.0000
14:92442707:TTCCA:T	acceptor_loss	1.0000
14:92442708:TCCA:T	acceptor_loss	1.0000
14:92442709:CCA:C	acceptor_loss	1.0000
14:92442710:CA:C	acceptor_loss	1.0000
14:92442711:A:AG	acceptor_gain	1.0000
14:92442711:AG:A	acceptor_gain	1.0000
14:92442711:AGG:A	acceptor_gain	1.0000
14:92442711:AGGG:A	acceptor_gain	1.0000
14:92442712:G:GG	acceptor_gain	1.0000
14:92442712:G:T	acceptor_loss	1.0000

AlphaMissense

4085 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:92439393:T:C	L126P	1.000
14:92442129:T:C	M145T	1.000
14:92442130:G:A	M145I	1.000
14:92442130:G:C	M145I	1.000
14:92442130:G:T	M145I	1.000
14:92442132:C:A	A146D	1.000
14:92442134:G:C	A147P	1.000
14:92442135:C:A	A147E	1.000
14:92442137:G:A	G148R	1.000
14:92442137:G:C	G148R	1.000
14:92442138:G:A	G148E	1.000
14:92442140:A:C	S149R	1.000
14:92442142:C:A	S149R	1.000
14:92442142:C:G	S149R	1.000
14:92442150:C:A	P152Q	1.000
14:92442150:C:G	P152R	1.000
14:92442156:T:C	L154P	1.000
14:92442752:T:A	I173N	1.000
14:92442757:G:C	G175R	1.000
14:92442757:G:T	G175C	1.000
14:92442758:G:A	G175D	1.000
14:92442758:G:T	G175V	1.000
14:92442769:T:C	F179L	1.000
14:92442771:C:A	F179L	1.000
14:92442771:C:G	F179L	1.000
14:92442774:C:A	N180K	1.000
14:92442774:C:G	N180K	1.000
14:92443431:G:C	R205P	1.000
14:92443433:G:C	D206H	1.000
14:92443434:A:C	D206A	1.000

dbSNP variants (sampled 300 via entrez): RS1000005176 (14:92469375 G>C,T), RS1000009832 (14:92323011 G>A,C,T), RS1000051723 (14:92360384 T>A), RS1000053802 (14:92454316 A>G), RS1000059066 (14:92473690 C>G), RS1000074746 (14:92354048 C>A,T), RS1000086645 (14:92430721 C>T), RS1000090826 (14:92354849 G>A,T), RS1000132834 (14:92475687 G>A), RS1000163225 (14:92392636 G>A), RS1000188817 (14:92430481 C>T), RS1000195014 (14:92338764 C>T), RS1000195688 (14:92437262 C>G,T), RS1000200979 (14:92421019 T>C), RS1000219831 (14:92412818 A>G)

Disease associations

OMIM: gene MIM:609840 | disease phenotypes: MIM:104500, MIM:615887

GenCC curated gene-disease

Disease	Classification	Inheritance
amelogenesis imperfecta hypomaturation type 2A5	Strong	Autosomal recessive
amelogenesis imperfecta, type 3A	Supportive	Autosomal dominant
amelogenesis imperfecta type 2	Supportive	Autosomal recessive

Mondo (4): amelogenesis imperfecta (MONDO:0019507), amelogenesis imperfecta hypomaturation type 2A5 (MONDO:0014385), amelogenesis imperfecta, type 3A (MONDO:0007538), amelogenesis imperfecta type 2 (MONDO:0015048)

Orphanet (1): Amelogenesis imperfecta (Orphanet:88661)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000670	Carious teeth
HP:0000705	Amelogenesis imperfecta
HP:0001595	Abnormal hair morphology
HP:0002164	Nail dysplasia
HP:0006286	Yellow-brown discoloration of the teeth
HP:0011463	Childhood onset

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST000117_1	Blue vs. green eyes	4.000000e-38
GCST000118_1	Blond vs. brown hair color	1.000000e-48
GCST000190_1	Black vs. blond hair color	8.000000e-21
GCST000707_2	Hair color	5.000000e-13
GCST000710_3	Eye color	2.000000e-23
GCST000710_5	Eye color	1.000000e-16
GCST001066_12	Dialysis-related mortality	8.000000e-06
GCST001066_5	Dialysis-related mortality	2.000000e-06
GCST001929_6	Eye color	4.000000e-11
GCST001929_8	Eye color	3.000000e-07
GCST001932_4	Hair color	2.000000e-36
GCST002245_20	Alzheimer’s disease (late onset)	6.000000e-09
GCST002817_14	Alzheimer’s disease in APOE e4- carriers	4.000000e-07
GCST003021_5	Brown vs. non-brown hair color	3.000000e-09
GCST003022_5	Light vs. dark hair color	3.000000e-10
GCST003023_4	Blond vs non-blond hair color	3.000000e-10
GCST003996_30	Monobrow	4.000000e-21
GCST005790_32	Rosacea symptom severity	5.000000e-06
GCST005965_3	B cell acute lymphoblastic leukaemia (normal cytogenetics)	6.000000e-09
GCST005966_3	B cell acute lymphoblastic leukaemia (hyperdiploid negative)	2.000000e-06
GCST005967_3	B cell acute lymphoblastic leukaemia (Philadelphia chromosome negative)	3.000000e-06
GCST006075_19	Hair color	1.000000e-100
GCST006988_117	Blond vs. brown/black hair color	1.000000e-09
GCST006988_130	Blond vs. brown/black hair color	9.000000e-15
GCST006988_142	Blond vs. brown/black hair color	9.000000e-13
GCST006989_38	Brown vs. black hair color	3.000000e-128
GCST007319_25	Alzheimer’s disease (late onset)	1.000000e-07
GCST007319_28	Alzheimer’s disease (late onset)	2.000000e-08
GCST007320_75	Alzheimer’s disease or family history of Alzheimer’s disease	2.000000e-10
GCST007320_94	Alzheimer’s disease or family history of Alzheimer’s disease	2.000000e-07

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0003949	eye color
EFO:0003924	hair color
EFO:0007906	synophrys measurement
EFO:0009180	rosacea severity measurement
EFO:0009268	family history of Alzheimer’s disease
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0006834	septic shock
EFO:0004530	triglyceride measurement
EFO:0007984	platelet component distribution width

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000567	Amelogenesis Imperfecta	C07.650.800.295.250; C07.793.700.295.250; C16.131.850.800.295.250
C536606	Amelogenesis Imperfecta hypomaturation type (supp.)
C562880	Amelogenesis Imperfecta, Type III (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5209636 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs77441273	SLC24A4		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC24 family of sodium/potassium/calcium exchangers

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases mutagenesis	2
bisphenol A	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
arsenite	decreases methylation	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Copper	affects cotreatment, decreases expression	1
Endosulfan	decreases expression	1
Environmental Pollutants	affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Rotenone	decreases expression	1
Silicon Dioxide	increases expression	1
Tretinoin	increases expression	1
Zidovudine	affects cotreatment, increases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5209621	Functional	Substrate uptake by the Sodium/Potassium/Calcium Exchanger 4 (NCKX4, SLC24A4) as assessed by Screen Questtrade mark Fluo-8 NW calcium assay kit in HEK-293 JumpIN-SLC24A4 cells (PubChem AID: 1794814)	Fluo-8 based assay for SLC24A4 using HEK293 JumpIn SLC24A4 OE cells

Clinical trials (associated diseases)

8 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01746121	Not specified	TERMINATED	Amelogenesis Imperfecta
NCT02994862	Not specified	UNKNOWN	E. Max Laminate Veneers With and Without Using Galla Chinnesis as Natural Cross Linking and Remineralizing Agent
NCT03810859	Not specified	UNKNOWN	Non-syndromic Inherited Anomalies of Mineralized Tooth Tissues: a Whole Exome Study to Identify New Pathogenic Variants
NCT04704089	Not specified	RECRUITING	Colorimetric, Ultra-structural and Elemental Comparison of Dental Enamel Defects
NCT04897724	Not specified	UNKNOWN	Clinical Performance of Composites in Patients With Amelogenesis Imperfecta
NCT04927962	Not specified	COMPLETED	Psycho-social Impact of Amelogenesis and Dentinogenesis Imperfecta
NCT05343247	Not specified	COMPLETED	Dental Age Estimation by Different Methods in Patients With Amelogenesis Imperfecta
NCT07250906	Not specified	RECRUITING	Oral Health Related Quality of Life of Children With Amelogenesis Imperfecta