ENAM

Summary

ENAM (enamelin, HGNC:3344) is a protein-coding gene on chromosome 4q13.3, encoding Enamelin (Q9NRM1). Involved in the mineralization and structural organization of enamel.

Dental enamel forms the outer cap of teeth and is the hardest substance found in vertebrates. This gene encodes the largest protein in the enamel matrix of developing teeth. The protein is involved in the mineralization and structural organization of enamel. Defects in this gene result in amelogenesis imperfect type 1C.

Source: NCBI Gene 10117 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amelogenesis imperfecta type 1B (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 326 total — 8 pathogenic, 5 likely-pathogenic (top 10% of genes corpus-wide)
• GTEx eGene: eQTL in 6 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 7
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.89 (unconstrained)
• MANE Select transcript: NM_031889

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3344
Approved symbol	ENAM
Name	enamelin
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000132464
Ensembl biotype	protein_coding
OMIM	606585
Entrez	10117

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

MANE Select: ENST00000396073

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 4: 1

ENST00000396073, ENST00000472597

RefSeq mRNA: 1 — MANE Select: NM_031889 NM_031889

CCDS: CCDS3544

Canonical transcript exons

ENST00000396073 — 9 exons

Exon	Start	End
ENSE00000850995	70642015	70646824
ENSE00000904382	70631670	70631738
ENSE00000904383	70631849	70631893
ENSE00000904384	70632651	70632692
ENSE00000904385	70634308	70634568
ENSE00000904386	70635832	70635894
ENSE00000904387	70637790	70637843
ENSE00001523768	70629441	70629554
ENSE00001523770	70628744	70628964

Expression profiles

Bgee: expression breadth broad, 83 present calls, max score 89.87.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1428 / max 16.4209, expressed in 56 samples.

Highest expression (Bgee): ventricle myocardium, cardiac muscle of right atrium, male germ line stem cell (sensu Vertebrata) in testis, kidney epithelium, islet of Langerhans.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ENAM is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 6 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

6 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Heart Atrial Appendage	eqtl	6.4e-04	-0.59	4:70636547:T:C
Stomach	eqtl	1.0e-03	+0.33	4:70615304:G:GCAAA
Artery Tibial	eqtl	1.8e-02	-0.27	4:70102540:G:T
Lung	eqtl	2.3e-02	+0.29	4:70174078:G:T
Cells EBV-transformed lymphocytes	eqtl	2.7e-02	+0.54	4:70994594:A:G
Adipose Subcutaneous	eqtl	3.0e-02	+0.17	4:70371238:CA:C

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
47988	0.1428	56

Top tissues by expression

showing 100 of 209 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	89.87	gold quality
cardiac muscle of right atrium	UBERON:0003379	89.06	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.45	gold quality
kidney epithelium	UBERON:0004819	83.73	silver quality
islet of Langerhans	UBERON:0000006	81.84	gold quality
vastus lateralis	UBERON:0001379	76.01	silver quality
quadriceps femoris	UBERON:0001377	75.34	silver quality
epithelial cell of pancreas	CL:0000083	74.13	gold quality
biceps brachii	UBERON:0001507	72.94	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	72.51	gold quality
skeletal muscle tissue	UBERON:0001134	72.30	gold quality
muscle tissue	UBERON:0002385	71.99	gold quality
adult mammalian kidney	UBERON:0000082	71.69	gold quality
deltoid	UBERON:0001476	69.72	silver quality
corpus epididymis	UBERON:0004359	69.07	gold quality
kidney	UBERON:0002113	69.03	gold quality
buccal mucosa cell	CL:0002336	68.67	gold quality
pancreas	UBERON:0001264	68.10	gold quality
colonic epithelium	UBERON:0000397	67.47	silver quality
gall bladder	UBERON:0002110	67.40	gold quality
hindlimb stylopod muscle	UBERON:0004252	66.77	gold quality
superficial temporal artery	UBERON:0001614	66.53	gold quality
heart right ventricle	UBERON:0002080	66.20	gold quality
gingival epithelium	UBERON:0001949	65.97	gold quality
muscle of leg	UBERON:0001383	65.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	65.70	silver quality
gastrocnemius	UBERON:0001388	65.47	gold quality
heart left ventricle	UBERON:0002084	65.45	gold quality
cardiac ventricle	UBERON:0002082	65.44	gold quality
cortex of kidney	UBERON:0001225	64.94	gold quality
cardiac atrium	UBERON:0002081	63.89	gold quality
upper arm skin	UBERON:0004263	63.43	gold quality
renal medulla	UBERON:0000362	63.01	gold quality
right atrium auricular region	UBERON:0006631	62.65	gold quality
heart	UBERON:0000948	62.28	gold quality
apex of heart	UBERON:0002098	61.84	gold quality
epithelium of mammary gland	UBERON:0003244	61.82	gold quality
mammary duct	UBERON:0001765	61.65	gold quality
body of pancreas	UBERON:0001150	61.27	gold quality
metanephros cortex	UBERON:0010533	60.87	gold quality
caput epididymis	UBERON:0004358	60.64	gold quality
layer of synovial tissue	UBERON:0007616	59.73	gold quality
gingiva	UBERON:0001828	58.96	gold quality
cardia of stomach	UBERON:0001162	58.87	gold quality
metanephros	UBERON:0000081	58.76	gold quality
mucosa of paranasal sinus	UBERON:0005030	58.67	gold quality
cerebellar vermis	UBERON:0004720	58.60	gold quality
subthalamic nucleus	UBERON:0001906	58.34	gold quality
nasal cavity epithelium	UBERON:0005384	58.27	gold quality
tibialis anterior	UBERON:0001385	57.60	silver quality
dorsal plus ventral thalamus	UBERON:0001897	57.49	gold quality
superior vestibular nucleus	UBERON:0007227	57.35	gold quality
body of tongue	UBERON:0011876	57.16	gold quality
ventral tegmental area	UBERON:0002691	57.12	gold quality
inferior vagus X ganglion	UBERON:0005363	56.98	gold quality
superior surface of tongue	UBERON:0007371	56.84	gold quality
thymus	UBERON:0002370	56.68	gold quality
tongue	UBERON:0001723	56.61	gold quality
medulla oblongata	UBERON:0001896	56.59	gold quality
saphenous vein	UBERON:0007318	56.51	gold quality
pericardium	UBERON:0002407	56.42	gold quality
trachea	UBERON:0003126	56.32	gold quality
synovial joint	UBERON:0002217	56.24	gold quality
cauda epididymis	UBERON:0004360	56.09	silver quality
nipple	UBERON:0002030	56.02	gold quality
dorsal root ganglion	UBERON:0000044	56.01	gold quality
pylorus	UBERON:0001166	55.82	gold quality
pons	UBERON:0000988	55.70	gold quality
penis	UBERON:0000989	55.70	gold quality
bone marrow cell	CL:0002092	55.55	gold quality
substantia nigra pars compacta	UBERON:0001965	55.46	gold quality
substantia nigra pars reticulata	UBERON:0001966	55.42	gold quality
lateral globus pallidus	UBERON:0002476	55.14	gold quality
lateral nuclear group of thalamus	UBERON:0002736	55.12	gold quality
pharyngeal mucosa	UBERON:0000355	55.08	gold quality
trigeminal ganglion	UBERON:0001675	54.49	gold quality
amniotic fluid	UBERON:0000173	54.30	gold quality
vena cava	UBERON:0004087	54.02	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	53.61	gold quality
epithelium of nasopharynx	UBERON:0001951	52.95	gold quality
stromal cell of endometrium	CL:0002255	52.12	silver quality
liver	UBERON:0002107	50.59	gold quality
nasal cavity mucosa	UBERON:0001826	50.09	gold quality
ileal mucosa	UBERON:0000331	49.96	silver quality
pancreatic ductal cell	CL:0002079	49.87	silver quality
stomach	UBERON:0000945	49.56	gold quality
body of stomach	UBERON:0001161	49.04	gold quality
urethra	UBERON:0000057	49.00	gold quality
smooth muscle tissue	UBERON:0001135	48.62	gold quality
oocyte	CL:0000023	48.56	gold quality
lower lobe of lung	UBERON:0008949	47.25	silver quality
right lobe of liver	UBERON:0001114	47.21	gold quality
tonsil	UBERON:0002372	46.55	gold quality
globus pallidus	UBERON:0001875	46.18	gold quality
bone marrow	UBERON:0002371	45.64	gold quality
duodenum	UBERON:0002114	45.25	silver quality
mucosa of stomach	UBERON:0001199	45.11	gold quality
popliteal artery	UBERON:0002250	45.03	gold quality
tibial artery	UBERON:0007610	44.97	gold quality
fundus of stomach	UBERON:0001160	44.84	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.13

HPA expression

RNA tissue specificity: Tissue enhanced

50 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Kidney	tissue	8.4
Epididymis	tissue	7.1
Heart muscle	tissue	6.1
Skeletal muscle	tissue	4.5
Pancreas	tissue	3.4
Gallbladder	tissue	2.2
Tongue	tissue	1.7
Stomach 1	tissue	1.6
Olfactory bulb	tissue	1.1
Cerebral cortex	tissue	1.0
Cerebellum	tissue	1.0
Periaqueductal gray	tissue	1.0
Insular cortex	tissue	1.0
Basal ganglia	tissue	0.9
Amygdala	tissue	0.9
Retrosplenial and cingulate cortex	tissue	0.9
Retrosplenial cortex	tissue	0.9
Temporal cortex	tissue	0.9
Prefrontal cortex	tissue	0.8
Corpus callosum	tissue	0.8
Hippocampal formation	tissue	0.8
Entorhinal cortex	tissue	0.8
Ventral forebrain	tissue	0.8
Occipital cortex	tissue	0.8
Motor cortex	tissue	0.7
Hypothalamus	tissue	0.7
Septum	tissue	0.7
Somatosensory cortex	tissue	0.7
Parathyroid gland	tissue	0.6
Putamen	tissue	0.6
Testis	tissue	0.5
Midbrain	tissue	0.5
Medulla oblongata	tissue	0.5
Thalamus	tissue	0.5
Superior colliculi	tissue	0.5
Substantia nigra	tissue	0.5
Spinal cord	tissue	0.5
Pons	tissue	0.4
Liver	tissue	0.4
Fallopian tube	tissue	0.3
Pituitary gland	tissue	0.2
Endometrium 1	tissue	0.2
Lung	tissue	0.2
Small intestine	tissue	0.2
Retina	tissue	0.1
Smooth muscle	tissue	0.1
Urinary bladder	tissue	0.1
Spleen	tissue	0.1
Duodenum	tissue	0.1
Hippocampus	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 10; highest nTPM — Ventral hippocampus (0.8), White matter (0.8), Dorsal hippocampus (0.7), Subiculum (0.7), Dorsal spinal cord (0.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, LEF1, SP3

miRNA regulators (miRDB)

Targeting ENAM by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 115 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-548AT-5P	99.96	70.83	2666

Functional genomics

gnomAD constraint: pLI 0.00118, LOEUF 0.892, missense Z 0.617 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000396073 — one region, missense o/e 1.02.

Literature-anchored findings (GeneRIF, showing 32)

• A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta (PMID:11978766)
• heterogeneous mutations are responsible for an autosomal-dominant hypoplastic form of amelogenesis imperfecta (PMID:12407086)
• critical for proper dental enamel formation (PMID:14656895)
• Demonstration of a ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel pitting. (PMID:14684688)
• Ultrastructural enamel changes in the patient with the autosomal dominant ENAM g.13185-13186insAG mutation, were less pronounced compared to ultrastructural changes in patients with the autosomal dominant ENAM mutation 8344delG. (PMID:17125728)
• A mutation was found in exon 9 where guanine was substituted by thymine in one of the alleles in position 817, generating a change of arginine to methionine in codon 179 of the protein. (PMID:17316551)
• This work shows that bursts of adaptive enamelin evolution occur on primate lineages with inferred dietary changes. (PMID:18245370)
• a single base difference g359A –> G located in exon 1 was identified and ruled out the possible mutation in exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, g2382, g6395 and g8344 of ENAM gene in the AI patient. (PMID:18466877)
• A total of 463 individuals from 54 families were evaluated and mutations in the AMEL, ENAM and KLK4 genes were identified. (PMID:18714142)
• Analysis revealed 2 ENAM mutations (autosomal-dominant g.14917delT and autosomal-recessive g.13185-13186insAG mutations). Single T deletion in exon 10 is a novel deletion mutation(g.14917delT, c.2991delT)predicted to result in premature termination codon. (PMID:19329462)
• The structure and composition of deciduous enamel affected by local hypoplastic autosomal dominant amelogenesis imperfecta resulting from an ENAM mutation (PMID:19923784)
• hypocalcified amelogenesis imperfecta, Witkop type III, was unrelated to previously described mutations in the ENAM or MMP-20 genes (PMID:21504268)
• Mutations in FAM83H and ENAM and related phenotypes were observed in Chinese families with amelogenesis imperfecta. (PMID:22414746)
• Associations between TFIP11 (p=0.02), ENAM (p=0.00001), and AMELX (p=0.01) could be seen with caries independent of having MIH or genomic DNA copies of Streptococcus mutans detected by real time PCR in the Brazilian sample. (PMID:23790503)
• 2 exonic SNPs, both changing an amino acid in protein region encoded by exon 10 (p.I648T and p.R763Q), increased caries susceptibility 2.66-fold. findings support ENAM as gene candidate for caries susceptibility. (PMID:24487377)
• Whole-exome sequencing identified 2 novel heterozygous nonsense mutations in the ENAM gene (c.454G>T p.Glu152* in family 1, c.358C>T p.Gln120* in family 2) in the probands. Affected individuals were heterozygous for the mutation in each family. (PMID:25143514)
• findings provide useful information for the implication of ENAM gene polymorphism in autosomal-dominant/-recessive amelogenesis imperfecta. (PMID:25427323)
• Screening of ENAM and LAMB3 genes was performed by direct sequencing of genomic DNA from blood samples. (PMID:25769099)
• Overrepresentation of the G allele of the enamelin marker was seen in the erosion group compared to the unaffected group. (PMID:25791822)
• The study revealed the strong association between rs12640848 marker of ENAM gene and caries susceptibility in primary teeth in children from Poland. (PMID:26910531)
• study investigated the phenotypic effect of SNP C14625T (rs7671281) on the thickness of human dental enamel, exploring the effects of positive selection on a dental gene (PMID:27357321)
• The ENAM and TNF-alpha genes were likely associated with caries occurrence in Chinese children. The ENAM rs3796703 CT and TNF-alpha rs1800629 AG genotypes might be involved in caries susceptibility and protection, respectively. (PMID:28395167)
• Among the variants shared with modern humans, two are ancestral (common with apes) and one is the derived enamelin major variant, T648I (rs7671281), associated with a thinner enamel and specific to the Homo lineage. (PMID:28902892)
• Lack of association between the ENAM polymorphism (rs12640848) and dental caries in Czech children was detected. (PMID:29185146)
• An ENAM nonsense mutation identified in a family with hypoplastic amelogenesis imperfecta resulted in a highly variable clinical phenotype in individuals with a heterozygous mutant allele. (PMID:29554435)
• Two novel ENAM frameshift mutations were identified. A single-nucleotide duplication replaced amino acids 133-1142 with a 12 amino acid sequence, and a single-nucleotide deletion replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). (PMID:31478359)
• ENAM Gene Variation in Students Exposed to Different Fluoride Concentrations. (PMID:32178265)
• ENAM gene associated with T classification and inhibits proliferation in renal clear cell carcinoma. (PMID:33539322)
• A novel ENAM mutation causes hypoplastic amelogenesis imperfecta. (PMID:33864320)
• Splicing mutations in AMELX and ENAM cause amelogenesis imperfecta. (PMID:37985977)
• Genetic variations in exon 10 of ENAM and their association with early childhood caries. (PMID:38642606)
• ENAM Mutations Can Cause Hypomaturation Amelogenesis Imperfecta. (PMID:38716742)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Enam	ENSMUSG00000029286
rattus_norvegicus	Enam	ENSRNOG00000003672

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1333772) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 47 distinct phenotype terms.

Mouse phenotype (MP)	Records
absent enamel	4
abnormal enamel morphology	3
abnormal incisor morphology	3
abnormal tooth morphology	2
reduced enamel thickness	2
abnormal molar morphology	2
abnormal incisor color	2
abnormal lower incisor morphology	2
abnormal upper incisor color	2
decreased bone mineral density	1
premature tooth eruption	1
abnormal trabecular bone morphology	1
decreased hematocrit	1
abnormal mouth morphology	1
decreased body length	1
decreased body weight	1
abnormal digestion	1
increased mean corpuscular volume	1
decreased circulating triglyceride level	1
abnormal enamel rod pattern	1
abnormal ameloblast morphology	1
abnormal tooth mineralization	1
decreased erythrocyte cell number	1
delayed tooth eruption	1
abnormal compact bone morphology	1

+22 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Sus scrofa	O97939	69.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
JCHAIN	protein-coding	3512
UTP3	protein-coding	57050
AMBN	protein-coding	258
AMTN	protein-coding	401138
MUC7	protein-coding	4589
ENAM-AS1	ncRNA	101927297
OPRPN	protein-coding	58503

Protein

Protein identifiers

Enamelin — Q9NRM1 (reviewed: Q9NRM1)

All UniProt accessions (2): A0A3B3ITB9, Q9NRM1

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the mineralization and structural organization of enamel. Involved in the extension of enamel during the secretory stage of dental enamel formation.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in tooth particularly in odontoblast, ameloblast and cementoblast.

Post-translational modifications. Phosphorylated by FAM20C in vitro.

Disease relevance. Amelogenesis imperfecta 1B (AI1B) [MIM:104500] An autosomal dominant defect of enamel formation. Clinical manifestations may be variable. Some cases present with generalized enamel hypoplasia resulting in small, smooth, yellow and widely spaced teeth (smooth hypoplastic AI). Others show horizontal rows of pits, grooves or a hypoplastic area in the enamel (local hypoplastic AI). The disease is caused by variants affecting the gene represented in this entry. Amelogenesis imperfecta 1C (AI1C) [MIM:204650] An autosomal recessive defect of dental enamel formation. Teeth show local hypoplastic and unmineralized enamel, and a yellow-brown discoloration. Enamel defects can be associated with facial and oral features including vertical dysgnathia and anterior openbite malocclusion. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_114095* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015673	Enamelin	Family

Pfam: PF15362

UniProt features (45 total): compositionally biased region 15, glycosylation site 10, region of interest 6, sequence variant 6, sequence conflict 3, modified residue 2, signal peptide 1, chain 1, mutagenesis site 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRM1-F1	36.63	0.00

Human Protein Atlas

Protein class: Predicted secreted proteins, Predicted intracellular proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Functional residue map

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

Post-translational modifications (2)

Type	Positions
Phosphoserine	191, 216

Glycosylation sites (10)

Type	Positions
N-linked (glcnac…) asparagine	114, 126, 245, 252, 265, 296, 467, 534, 934, 1040

Mutagenesis-validated functional residues (1)

Position	Phenotype
191	decreased phosphorylation by fam20c.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-8957275	Post-translational protein phosphorylation	curated
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	curated
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—

MSigDB gene sets: 110 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_TOOTH_MINERALIZATION, chr4q13, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_ENAMEL_MINERALIZATION, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, WTGAAAT_UNKNOWN, GOBP_AMELOGENESIS, GOBP_COLUMNAR_CUBOIDAL_EPITHELIAL_CELL_DIFFERENTIATION, POU3F2_02, GOBP_ODONTOGENESIS_OF_DENTIN_CONTAINING_TOOTH, GOBP_POSITIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_ODONTOGENESIS, GOCC_ENDOPLASMIC_RETICULUM_LUMEN, YATGNWAAT_OCT_C

GO Biological Process (4): biomineral tissue development (GO:0031214), ameloblast differentiation (GO:0036305), positive regulation of enamel mineralization (GO:0070175), amelogenesis (GO:0097186)

GO Molecular Function (2): structural constituent of tooth enamel (GO:0030345), protein binding (GO:0005515)

GO Cellular Component (2): endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Metabolism of proteins	2
Post-translational protein modification	1

GO top-level categories

13 GO namespaces:

Category	Terms
tissue development	1
animal organ development	1
columnar/cuboidal epithelial cell differentiation	1
enamel mineralization	1
positive regulation of tooth mineralization	1
regulation of enamel mineralization	1
odontogenesis of dentin-containing tooth	1
anatomical structure formation involved in morphogenesis	1
extracellular matrix structural constituent conferring compression resistance	1
binding	1
endoplasmic reticulum	1
intracellular organelle lumen	1
external encapsulating structure	1

Protein interactions and networks

STRING

showing 15 of 764 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENAM	AMBN	Q9NP70	993
ENAM	AMTN	Q6UX39	987
ENAM	AMELX	Q99217	979
ENAM	TUFT1	Q9NNX1	959
ENAM	KLK4	Q9Y5K2	895
ENAM	MMP20	O60882	882
ENAM	ODAM	A1E959	838
ENAM	DSPP	Q9NZW4	837
ENAM	SACK1H	Q6ZRV2	811
ENAM	WDR72	Q3MJ13	777
ENAM	ODAPH	Q17RF5	758
ENAM	ACP4	Q9BZG2	725
ENAM	MMP25	Q9NPA2	717
ENAM	FAM20A	Q96MK3	695
ENAM	AMELY	Q99218	671

IntAct

Human interaction partners of ENAM in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
FAM20C	phosphorylation reaction	0.440	2
NCL	physical association	0.400	1

BioGRID (6 interactions; top human partners by supporting records): EEA1 (Cross-Linking-MS (XL-MS)), NEK4 (Affinity Capture-MS), NUDT21 (Affinity Capture-RNA), SIK2 (Affinity Capture-MS), TNKS (Proximity Label-MS), TOPBP1 (Proximity Label-MS)

Disease & clinical

Genetic variants

Variant evidence for ENAM: 326 ClinVar records (13 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	5
Uncertain significance	236
Likely benign	35
Benign	23

Top pathogenic / likely-pathogenic (13)

Showing all 13 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1192504	NM_031889.3(ENAM):c.588+1del	Pathogenic	criteria provided, multiple submitters, no conflicts	3
2445233	NM_031889.3(ENAM):c.664C>T (p.Gln222Ter)	Pathogenic	criteria provided, single submitter	1
4813874	NM_031889.3(ENAM):c.1083G>A (p.Trp361Ter)	Pathogenic	criteria provided, single submitter	1
2440040	NM_031889.3(ENAM):c.372_382del (p.Lys124fs)	Likely pathogenic	criteria provided, single submitter	1
2628824	NM_031889.3(ENAM):c.107del (p.Asn36fs)	Likely pathogenic	criteria provided, single submitter	1
2690595	NM_031889.3(ENAM):c.935_944del (p.Ser312fs)	Likely pathogenic	criteria provided, single submitter	1
4967323	NM_031889.3(ENAM):c.652G>T (p.Glu218Ter)	Likely pathogenic	criteria provided, single submitter	1
4967332	NM_031889.3(ENAM):c.1883del (p.Asn628fs)	Likely pathogenic	criteria provided, single submitter	1
4236	NM_031889.3(ENAM):c.534+1G>A	Pathogenic	no assertion criteria provided	1
4237	NM_031889.3(ENAM):c.157A>T (p.Lys53Ter)	Pathogenic	no assertion criteria provided	1
488662	NM_031889.3(ENAM):c.1842C>G (p.Tyr614Ter)	Pathogenic	no assertion criteria provided	1
517662	NM_031889.3(ENAM):c.123+2T>G	Pathogenic	no assertion criteria provided	1
1012267	NM_031889.3(ENAM):c.-61+1G>A	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ENAM’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 41 predictions of 552):

Position(s)	Effect	Δscore	Sites
4:70632649–70632650	acceptor_loss	1.0000	4
4:70632693–70632694	donor_loss	1.0000	5
4:70634306–70634307	acceptor_loss	1.0000	2
4:70635830–70635831	acceptor_loss	1.0000	6
4:70631739–70631740	donor_loss	0.9900	5
4:70631743	donor_loss	0.9900	3
4:70632649	acceptor_loss	0.9900	2
4:70634306–70634307	acceptor_loss	0.9900	4
4:70634569–70634570	donor_loss	0.9900	5
4:70635895–70635896	donor_loss	0.9900	5

AlphaMissense

603 missense substitutions predicted likely pathogenic (of 7,576 scored), across 155 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M219	9	0.775	0.916
E56	7	0.942	0.980
F50	7	0.928	0.986
E55	7	0.928	0.978
F200	7	0.918	0.976
S54	7	0.909	0.987
F208	7	0.893	0.954
E218	7	0.893	0.946
S52	7	0.886	0.987
F220	7	0.883	0.959
C1057	7	0.877	0.922
F203	7	0.872	0.959
E217	7	0.856	0.949
F63	7	0.841	0.956
E193	7	0.836	0.934
C874	7	0.810	0.870
C1137	7	0.801	0.894
F162	7	0.793	0.941
C875	7	0.736	0.808
D223	7	0.732	0.857

HPA cancer prognostics

RNA cancer specificity: Group enriched (Kidney Chromophobe, Kidney Renal Clear Cell Carcinoma, Kidney Renal Papillary Cell Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	3.02e-09
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000933

Disease associations

OMIM: gene MIM:606585 | disease phenotypes: MIM:104500, MIM:204650

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
amelogenesis imperfecta type 1B	Definitive	Autosomal dominant	3
amelogenesis imperfecta type 1C	Strong	Autosomal recessive	2
amelogenesis imperfecta type 1	Strong	Semidominant	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
Amelogenesis imperfecta	green

Mondo (4): amelogenesis imperfecta (MONDO:0019507), amelogenesis imperfecta type 1B (MONDO:0007092), amelogenesis imperfecta type 1C (MONDO:0008770), amelogenesis imperfecta type 1 (MONDO:0015047)

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

HPO phenotypes

7 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000679	Taurodontia
HP:0000705	Amelogenesis imperfecta
HP:0006285	Enamel hypomineralization
HP:0006286	Yellow-brown discoloration of the teeth
HP:0009102	Anterior open-bite malocclusion

GWAS associations

1 associations:

Study	Trait	p-value
GCST009531_3	Body fat percentage	5e-8

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0007800	body fat percentage

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D000567	Amelogenesis Imperfecta	C07.650.800.295.250; C07.793.700.295.250; C16.131.850.800.295.250
C562879	Amelogenesis Imperfecta, Type IB *(supp.)*
C567147	Amelogenesis Imperfecta, Type Ic *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation	1
cupric chloride	affects expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

8 trials:

NCT	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	COMPLETED	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