AMELY

Summary

AMELY (amelogenin Y-linked, HGNC:462) is a protein-coding gene on chromosome Yp11.2, encoding Amelogenin, Y isoform (Q99218). Plays a role in biomineralization.

This gene encodes a member of the amelogenin family of extracellular matrix proteins. Amelogenins are involved in biomineralization during tooth enamel development. Mutations in a related gene on chromosome X cause X-linked amelogenesis imperfecta.

Source: NCBI Gene 266 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 67 total — 43 pathogenic
• MANE Select transcript: NM_001143

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:462
Approved symbol	AMELY
Name	amelogenin Y-linked
Location	Yp11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000099721
Ensembl biotype	protein_coding
OMIM	410000
Entrez	266

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000383036, ENST00000651267

RefSeq mRNA: 2 — MANE Select: NM_001143 NM_001143, NM_001364814

CCDS: CCDS14778, CCDS94708

Canonical transcript exons

ENST00000651267 — 7 exons

Exon	Start	End
ENSE00000652250	6868732	6868776
ENSE00001494454	6865918	6866078
ENSE00001645681	6870006	6870053
ENSE00001667251	6868037	6868462
ENSE00001671586	6872555	6872620
ENSE00003842130	6873972	6874071
ENSE00003845700	6911673	6911752

Expression profiles

Bgee: expression breadth broad, 20 present calls, max score 83.18.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.18	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.11	gold quality
triceps brachii	UBERON:0001509	76.55	gold quality
gluteal muscle	UBERON:0002000	76.24	gold quality
heart right ventricle	UBERON:0002080	68.10	gold quality
pancreatic ductal cell	CL:0002079	65.97	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	63.82	gold quality
orbitofrontal cortex	UBERON:0004167	61.13	gold quality
Brodmann (1909) area 46	UBERON:0006483	60.55	gold quality
tibialis anterior	UBERON:0001385	60.20	silver quality
biceps brachii	UBERON:0001507	59.83	gold quality
nasal cavity epithelium	UBERON:0005384	58.74	gold quality
deltoid	UBERON:0001476	58.06	gold quality
inferior olivary complex	UBERON:0002127	57.34	gold quality
endothelial cell	CL:0000115	56.87	gold quality
decidua	UBERON:0002450	56.55	gold quality
jejunal mucosa	UBERON:0000399	55.71	gold quality
quadriceps femoris	UBERON:0001377	55.14	gold quality
myocardium	UBERON:0002349	54.65	gold quality
colonic mucosa	UBERON:0000317	54.18	gold quality
vastus lateralis	UBERON:0001379	54.03	gold quality
cranial nerve II	UBERON:0000941	53.18	silver quality
mucosa of sigmoid colon	UBERON:0004993	53.00	gold quality
ileal mucosa	UBERON:0000331	52.90	silver quality
hair follicle	UBERON:0002073	52.43	gold quality
epithelial cell of pancreas	CL:0000083	52.23	gold quality
skeletal muscle tissue	UBERON:0001134	51.95	gold quality
upper leg skin	UBERON:0004262	51.68	silver quality
seminal vesicle	UBERON:0000998	51.65	gold quality
muscle tissue	UBERON:0002385	50.83	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.35

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, YY1

miRNA regulators (miRDB)

16 targeting AMELY, 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-548P	99.98	72.25	3784
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-508-3P	98.66	69.62	887
HSA-MIR-934	98.49	70.44	581
HSA-MIR-4421	97.99	64.89	701
HSA-MIR-5699-3P	97.81	65.00	861

Literature-anchored findings (GeneRIF, showing 7)

• Multigene deletions encompassing AMELY on short arm of chromosome Y. (PMID:17189292)
• The combined frequency of the AMELY null allele in Singapore and Malaysia populations is 2.7%, 0.6% in Indian and Malay ethnic groups respectively. It is absent among 541 Chinese screened. (PMID:17588179)
• Results of haplogroup prediction showed that seven AMELY dropouts combined with variant Y-STR deletions can be classified as the J2 subdivision, suggesting that some of these Y chromosomes might descend from a common ancestor. (PMID:22669323)
• 252 confirmed and unrelated father/son pairs from the Moroccan population were examined using 17 Y-STR markers of the AmpFISTR Yfiler kit. A total of 15 single repeat mutations between fathers and sons were observed as mutational events. (PMID:23623014)
• demonstrate the presence of copy number variations in regions containing 9 of the 13 CODIS(Combined DNA Index System) short tandem repeat(STR) and AMELX/Y loci (PMID:23948316)
• Finally, since these results are almost completely in accordance with previously published data on B&H and neighboring populations generated by Y-chromosome single nucleotide polymorphism analysis, it can be concluded that in silico analysis of Y-STRs is a reliable method for approximation of the Y-chromosome haplogroup diversity of an examined population. (PMID:28828942)
• Optimization of Method for Human Sex Determination Using Peptidome Analysis of Teeth Enamel from Teeth of Different Biological Generation, Archeological Age, and Degrees of Taphonomic Preservation. (PMID:32571191)

Cross-species orthologs

0 orthologs

Paralogs (1): AMELX (ENSG00000125363)

Protein

Protein identifiers

Amelogenin, Y isoform — Q99218 (reviewed: Q99218)

All UniProt accessions (1): Q99218

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in biomineralization. Seems to regulate the formation of crystallites during the secretory stage of tooth enamel development. Thought to play a major role in the structural organization and mineralization of developing enamel.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Similarity. Belongs to the amelogenin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99218-2	2	yes
Q99218-1	1

RefSeq proteins (2): NP_001134, NP_001351743 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004116	Amelogenin	Family

Pfam: PF02948

UniProt features (8 total): compositionally biased region 2, sequence conflict 2, signal peptide 1, chain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99218-F1	57.18	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 60 (showing top): GOBP_TOOTH_MINERALIZATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_ENAMEL_MINERALIZATION, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, TGCTGAY_UNKNOWN, GOBP_AMELOGENESIS, MODULE_88, MODULE_113, GOBP_ODONTOGENESIS_OF_DENTIN_CONTAINING_TOOTH, MODULE_400, PITX2_Q2, MODULE_112, MCCABE_HOXC6_TARGETS_UP, GOBP_ODONTOGENESIS, MODULE_55

GO Biological Process (3): enamel mineralization (GO:0070166), multicellular organism development (GO:0007275), biomineral tissue development (GO:0031214)

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

GO Cellular Component (3): extracellular matrix (GO:0031012), extracellular region (GO:0005576), obsolete collagen-containing extracellular matrix (GO:0062023)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
tooth mineralization	1
amelogenesis	1
multicellular organismal process	1
anatomical structure development	1
tissue development	1
animal organ development	1
extracellular matrix structural constituent conferring compression resistance	1
binding	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

566 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AMELY	TSPY1	P09002	967
AMELY	PRKY	O43930	961
AMELY	TBL1Y	Q9BQ87	931
AMELY	A0A087WUC5	A0A087WUC5	928
AMELY	PCDH11X	Q9BZA7	845
AMELY	PRKX	P51817	819
AMELY	ENAM	Q9NRM1	798
AMELY	ZFY	P08048	783
AMELY	OSTC	Q9NRP0	764
AMELY	SRY	Q05066	729
AMELY	AMBN	Q9NP70	664
AMELY	USP9Y	O00507	655
AMELY	UTY	O14607	643
AMELY	RPS4Y1	P22090	623
AMELY	TMSB4Y	O14604	608

IntAct

1 interactions, top by confidence:

BioGRID (1): HIBADH (Two-hybrid)

ESM2 similar proteins: A1E959, A1E960, A1YQ91, A1YQ92, A1YQ93, A1YQ94, B3A0S0, B5DRT7, O55189, O62823, P02661, P02662, P02665, P02668, P02669, P02670, P04653, P06796, P10598, P11840, P11841, P18626, P19228, P19442, P33618, P39035, P39037, P42155, P42156, P42157, P50420, P50421, P50422, P50423, P50424, P50425, P63277, P63278, Q003G9, Q27002

Diamond homologs: O97646, O97647, P02817, P45561, P63277, P63278, Q28462, Q861X8, Q99004, Q99217, Q99218, Q9Z0K9, P12761

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	0
Uncertain significance	9
Likely benign	12
Benign	0

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
144190	GRCh37/hg19 Yp11.31-q12(chrY:2654852-59031480)x3	Pathogenic
144552	GRCh38/hg38 Yp11.2-q11.222(chrY:6255441-18435984)x2	Pathogenic
145476	GRCh38/hg38 Yp11.2-q11.23(chrY:6270281-26463761)x0	Pathogenic
146874	GRCh38/hg38 Yp11.2-q11.23(chrY:2786596-26575961)x0	Pathogenic
147693	GRCh38/hg38 Yp11.2-q11.23(chrY:2855704-24288951)x2	Pathogenic
149400	GRCh37/hg19 Yp11.31-q12(chrY:2650559-59032389)x2	Pathogenic
150476	GRCh38/hg38 Yp11.2-q12(chrY:2133003-56884424)x0	Pathogenic
151963	GRCh38/hg38 Yp11.2-q11.222(chrY:2782272-17454794)x2	Pathogenic
1676302	GRCh37/hg19 Yp11.31-q11.23(chrY:2650424-28799654)	Pathogenic
1703659	GRCh37/hg19 Yp11.32-q12(chrY:1-59373566)	Pathogenic
1708270	GRCh37/hg19 Yp11.31-11.2(chrY:2650140-9651417)x1	Pathogenic
253428	GRCh37/hg19 Yp11.32-q12(chrY:20297-59358845)x2	Pathogenic
253481	GRCh37/hg19 Yp11.32-q12(chrY:126426-59349649)x2	Pathogenic
253518	GRCh37/hg19 Yp11.32-q12(chrY:21267-59349649)x2	Pathogenic
253542	GRCh37/hg19 Yp11.32-q12(chrY:21267-59337042)x2	Pathogenic
253556	GRCh37/hg19 Yp11.32-q11.221(chrY:100002-15906224)x2	Pathogenic
253609	GRCh37/hg19 Yp11.32-q12(chrY:126426-59353228)x2	Pathogenic
253625	GRCh37/hg19 Yp11.32-q12(chrY:10701-59349277)x1	Pathogenic
253653	GRCh37/hg19 Yp11.32-q12(chrY:100002-59353228)x2	Pathogenic
3148873	GRCh37/hg19 Yp11.31-q11.222(chrY:2650425-20609790)x2	Pathogenic
395689	GRCh37/hg19 Yp11.32-q12(chrY:20297-59356174)	Pathogenic
441580	GRCh37/hg19 Yp11.32-q11.23(chrY:168546-28451874)x1	Pathogenic
564967	GRCh37/hg19 Yp11.31-q11.221(chrY:2650140-15125858)x0	Pathogenic
564968	GRCh37/hg19 Yp11.32-q11.1(chrY:168807-13134517)x1,2	Pathogenic
564969	GRCh37/hg19 Yp11.31-q11.223(chrY:2650140-24070172)x2	Pathogenic
57173	GRCh38/hg38 Yp11.2-q11.223(chrY:2788370-20525326)x2	Pathogenic
57270	GRCh38/hg38 Yp11.2-q11.223(chrY:2786811-22358529)x2	Pathogenic
57321	GRCh38/hg38 Yp11.2(chrY:2786811-9007152)x2	Pathogenic
58764	GRCh38/hg38 Yp11.2-q12(chrY:2783624-26637948)x2	Pathogenic
58793	GRCh38/hg38 Yp11.2-q11.221(chrY:2783624-13011793)x2	Pathogenic

SpliceAI

857 predictions. Top by Δscore:

Variant	Effect	Δscore
Y:6868730:A:AC	donor_gain	1.0000
Y:6868731:C:CC	donor_gain	1.0000
Y:6872553:A:AC	donor_gain	1.0000
Y:6872554:C:CC	donor_gain	1.0000
Y:6872554:CAGG:C	donor_gain	1.0000
Y:6870057:T:C	acceptor_gain	0.9900
Y:6872546:TTTAC:T	donor_loss	0.9900
Y:6872547:TTACT:T	donor_loss	0.9900
Y:6872548:TAC:T	donor_loss	0.9900
Y:6872549:AC:A	donor_loss	0.9900
Y:6872551:TCACA:T	donor_loss	0.9900
Y:6872552:CA:C	donor_loss	0.9900
Y:6872553:ACAGG:A	donor_gain	0.9900
Y:6872554:CA:C	donor_gain	0.9900
Y:6872554:CAG:C	donor_gain	0.9900
Y:6872554:CAGGC:C	donor_gain	0.9900
Y:6872621:C:CC	acceptor_gain	0.9900
Y:6873968:ATAC:A	donor_loss	0.9900
Y:6873969:TAC:T	donor_loss	0.9900
Y:6873970:A:AT	donor_loss	0.9900
Y:6868463:C:CC	acceptor_gain	0.9800
Y:6870057:T:TC	acceptor_gain	0.9800
Y:6870059:A:AC	acceptor_gain	0.9800
Y:6872618:GTTCT:G	acceptor_loss	0.9800
Y:6872620:TC:T	acceptor_loss	0.9800
Y:6872622:T:G	acceptor_loss	0.9800
Y:6873970:A:AC	donor_gain	0.9800
Y:6873971:C:CC	donor_gain	0.9800
Y:6910983:G:GA	donor_loss	0.9800
Y:6910984:T:A	donor_loss	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000181973 (Y:6876460 G>A), RS1000712407 (Y:6874942 A>G), RS1000740882 (Y:6899357 G>A), RS1001005503 (Y:6898018 C>G), RS1001365595 (Y:6886292 G>C), RS1001903946 (Y:6870293 T>C), RS1002267379 (Y:6890665 T>C), RS1002385553 (Y:6868376 G>A), RS1002409234 (Y:6891896 G>A), RS1002461662 (Y:6892978 G>A), RS1002967654 (Y:6910962 A>G), RS1003034337 (Y:6884512 C>G), RS1003065405 (Y:6884196 C>G), RS1003327782 (Y:6909676 T>A), RS1004068193 (Y:6911069 C>G,T)

Disease associations

OMIM: gene MIM:410000 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): Klinefelter syndrome (MONDO:0006823), male infertility (MONDO:0005372)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430
D007713	Klinefelter Syndrome	C12.050.351.875.253.795.500; C12.200.706.316.795.500; C12.800.316.795.500; C16.131.260.830.835.500; C16.131.939.316.795.500; C16.320.180.830.835.500; C19.391.119.795.500; C19.391.482.629

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
arsenite	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	affects methylation	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02408445	PHASE4	COMPLETED	Body Composition in Infants With Klinefelter Syndrome and Effects of Testosterone Treatment
NCT03325647	PHASE4	COMPLETED	TESTO: Testosterone Effects on Short-Term Outcomes in Infants With XXY
NCT05498090	PHASE4	UNKNOWN	Interrogating Fatty Acid Metabolism Impairment and Clinical Correlates in Males with Klinefelter Syndrome
NCT06294990	PHASE4	RECRUITING	Klinefelter Syndrome and Testosterone Treatment in Puberty
NCT02202382	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Male Infertility
NCT02204826	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients: a Randomized, Placebo-controlled, Double-blind Clinical Study
NCT03802864	PHASE4	COMPLETED	Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine
NCT06100432	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Eurycoma Longifolia (DLBS5055) and Multivitamins (Vitamin C+Vitamin E+ β-carotene) for Infertile Males
NCT07523022	PHASE4	ENROLLING_BY_INVITATION	Comparison of the Effect of Gonadotropin and Clomiphene Citrate Treatment on Sperm Parameters and the Outcome of Assisted Reproductive Procedures in Subfertile Men Based on the APHRODITE Groups
NCT05586802	PHASE3	RECRUITING	Sex Steroids Balance for Metabolic and Reproductive Health in Klinefelter Syndrome
NCT00975117	PHASE3	COMPLETED	Spermotrend in the Treatment of Male Infertility
NCT01407432	PHASE3	COMPLETED	Impact of Folates in the Care of the Male Infertility
NCT01895816	PHASE3	COMPLETED	Herbal Tonic Fertile Supplement(ZO2C5)
NCT02605070	PHASE3	TERMINATED	Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia
NCT07402759	PHASE3	ACTIVE_NOT_RECRUITING	Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men
NCT00348946	PHASE2	COMPLETED	Androgen Effect on Klinefelter Syndrome Motor Outcome
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT01880086	PHASE2	COMPLETED	Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
NCT02421887	PHASE2	COMPLETED	Males, Antioxidants, and Infertility Trial
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT05290558	PHASE2	ACTIVE_NOT_RECRUITING	The Therapeutic Effects of Bu Shen Yi Jing Pill on Semen Quality in Sub Fertile Males: a Randomized Controlled Trial
NCT06091969	PHASE2	NOT_YET_RECRUITING	Supplementation for Male Subfertility
NCT01595308	PHASE1	COMPLETED	A Pilot Study to Evaluate the Effect of Pomegranate Juice on Semen Parameters in Healthy Male Volunteers
NCT02122211	PHASE1	COMPLETED	Choline Dehydrogenase and Sperm Function: Effects of Betaine
NCT02575924	PHASE1	UNKNOWN	Influence of Culture Media on Clinical Outcomes in Poor Responders or Severe Male Infertility
NCT01206270	PHASE2/PHASE3	COMPLETED	Androgen for Leydig Cell Proliferation
NCT00347464	Not specified	WITHDRAWN	Adaptive Behavior Assessment of Men With 49, XXXXY, Klinefelter Syndrome
NCT00523835	Not specified	COMPLETED	Body Composition, Bone Mineral Density, Insulin Sensitivity and Echocardiographic Measurements in Klinefelter Syndrome
NCT00891852	Not specified	UNKNOWN	Non-Invasive Determination of Fetal Chromosome Abnormalities
NCT00896272	Not specified	COMPLETED	Adaptation Among Adolescents and Adults With Klinefelter Syndrome
NCT00999310	Not specified	COMPLETED	Neuropsychologic, Neuroradiologic, Endocrinologic, and Genetic Aspects of Klinefelter Syndrome
NCT01585831	Not specified	COMPLETED	Study of Psychological and Motor Effects of Testosterone in Adolescents With XXY/Klinefelter Syndrome
NCT01678261	Not specified	COMPLETED	X-chromosome Inactivation, Epigenetics and the Transcriptome
NCT01690013	Not specified	COMPLETED	Life Quality and Health in Patients With Klinefelter Syndrome
NCT01750632	Not specified	COMPLETED	Subcapsular Orchiectomy in Men With Klinefelter Syndrome
NCT01817296	Not specified	COMPLETED	Klinefelter Fertility Preservation
NCT01918280	Not specified	COMPLETED	Fertility Preservation in Cases of Klinefelter Syndrome.
NCT02414295	Not specified	COMPLETED	Sperm Production in Kleinfelter Syndrome Patients After Mesenchymal Stem Cell Injection
NCT02430584	Not specified	UNKNOWN	Whole Blood Specimen Collection From Pregnant Subjects
NCT02461303	Not specified	TERMINATED	Fertility Assessment in Patients With Klinefelter Syndrome