A2ML1

Summary

A2ML1 (alpha-2-macroglobulin like 1, HGNC:23336) is a protein-coding gene on chromosome 12p13.31, encoding Alpha-2-macroglobulin-like protein 1 (A8K2U0). Is able to inhibit all four classes of proteinases by a unique ’trapping’ mechanism.

This gene encodes a member of the alpha-macroglobulin superfamily. The encoded protein is thought to be an N-glycosylated monomeric protein that acts as an inhibitor of several proteases. It has been shown to form covalent interactions with proteases, and has been reported as the p170 antigen recognized by autoantibodies in the autoimmune disease paraneoplastic pemphigus (PNP; PMID:20805888). Mutations in these gene have also been associated with some cases of Noonan syndrome (NS; PMID:24939586) as well as some cases of otitis media (PMID:26121085). Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 144568 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Supportive, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 1,986 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 3
• MANE Select transcript: NM_144670

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23336
Approved symbol	A2ML1
Name	alpha-2-macroglobulin like 1
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25179, p170
Ensembl gene	ENSG00000166535
Ensembl biotype	protein_coding
OMIM	610627
Entrez	144568

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000299698, ENST00000536789, ENST00000537475, ENST00000537546, ENST00000539547, ENST00000540049, ENST00000541459, ENST00000545692, ENST00000545850

RefSeq mRNA: 2 — MANE Select: NM_144670 NM_001282424, NM_144670

CCDS: CCDS73439, CCDS8596

Canonical transcript exons

ENST00000299698 — 36 exons

Exon	Start	End
ENSE00001104123	8869135	8869203
ENSE00001275357	8851784	8852012
ENSE00001294346	8868537	8868627
ENSE00001348621	8874971	8875012
ENSE00001348672	8868230	8868357
ENSE00001373024	8848720	8848914
ENSE00001378613	8852210	8852336
ENSE00001382865	8849669	8849759
ENSE00001387925	8850160	8850274
ENSE00001417077	8867842	8868057
ENSE00001420883	8860881	8860955
ENSE00001422172	8874425	8874527
ENSE00001490726	8863794	8864008
ENSE00001490727	8861135	8861297
ENSE00001490728	8857946	8858102
ENSE00001490729	8857507	8857588
ENSE00001490730	8857164	8857340
ENSE00001490731	8855509	8855592
ENSE00001490732	8854780	8854831
ENSE00001490733	8854128	8854249
ENSE00001613147	8835507	8835666
ENSE00001688891	8839113	8839222
ENSE00001699012	8838336	8838450
ENSE00001748587	8841369	8841536
ENSE00001758815	8823182	8823365
ENSE00001761740	8837440	8837566
ENSE00001781558	8836255	8836339
ENSE00001792539	8834662	8834682
ENSE00001793606	8843134	8843361
ENSE00001798845	8845442	8845502
ENSE00002221116	8876058	8876787
ENSE00002227259	8822621	8822713
ENSE00003503132	8829727	8829779
ENSE00003532089	8823720	8823882
ENSE00003638209	8847549	8847698
ENSE00003682661	8846077	8846222

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 99.53.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.9552 / max 422.0574, expressed in 118 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124003	1.5811	84
124002	0.1494	41
124004	0.1079	22
124000	0.0431	13
124001	0.0386	17
124005	0.0332	15
124007	0.0013	1
124006	0.0006	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.53	gold quality
gingiva	UBERON:0001828	98.89	gold quality
gingival epithelium	UBERON:0001949	98.77	gold quality
esophagus mucosa	UBERON:0002469	98.72	gold quality
esophagus squamous epithelium	UBERON:0006920	98.44	gold quality
pharyngeal mucosa	UBERON:0000355	98.09	gold quality
oral cavity	UBERON:0000167	98.02	gold quality
body of tongue	UBERON:0011876	97.28	gold quality
penis	UBERON:0000989	96.77	gold quality
skin of abdomen	UBERON:0001416	95.64	gold quality
skin of leg	UBERON:0001511	95.44	gold quality
buccal mucosa cell	CL:0002336	94.07	gold quality
zone of skin	UBERON:0000014	93.64	gold quality
mammalian vulva	UBERON:0000997	92.22	gold quality
tongue	UBERON:0001723	91.77	gold quality
amniotic fluid	UBERON:0000173	91.49	gold quality
vagina	UBERON:0000996	90.17	gold quality
superior surface of tongue	UBERON:0007371	85.09	gold quality
oocyte	CL:0000023	85.00	gold quality
upper leg skin	UBERON:0004262	84.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.44	gold quality
tonsil	UBERON:0002372	82.18	gold quality
esophagus	UBERON:0001043	80.80	gold quality
nipple	UBERON:0002030	78.78	gold quality
epithelium of nasopharynx	UBERON:0001951	78.60	gold quality
right testis	UBERON:0004534	78.14	gold quality
left testis	UBERON:0004533	76.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.12	gold quality
mouth mucosa	UBERON:0003729	75.12	gold quality
secondary oocyte	CL:0000655	75.09	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10596	yes	418.06
E-ANND-3	yes	9.72

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

35 targeting A2ML1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-502-5P	98.77	66.51	906
HSA-MIR-4317	98.49	67.09	987
HSA-MIR-4662A-5P	98.48	67.18	1007
HSA-MIR-6841-3P	98.08	66.54	604
HSA-MIR-4759	97.39	65.86	608
HSA-MIR-517-5P	97.13	68.43	781

Literature-anchored findings (GeneRIF, showing 14)

• alpha2ML1 is the first alpha2macroglobulin family member detected in the epidermis, where it may play an important role during desquamation by inhibiting extracellular proteases. (PMID:16298998)
• alpha2ML1 binding to the low density lipoprotein receptor-related protein 1 (LRP1) reveals a new role for LRP1 in the human epidermis (PMID:18648652)
• a new class of target antigens in a paraneoplastic autoimmune multiorgan syndrome (PMID:20805888)
• our results provide evidence that mutations in A2ML1 are a cause of Noonan-like syndrome, with a variable phenotype ranging from severe to very mild. (PMID:24939586)
• Studies support a role for alpha-2-macroglobulin-like 1 protein (A2ML1) in the pathophysiology of otitis media. (PMID:26121085)
• The indigenous Filipino population has a ~50% prevalence of otitis media. A2ML1 genotype is the primary risk factor for otitis media and main determinant of disease progression, although age, the middle ear microbiome, and social clusters might modulate the effect of the A2ML1 genotype. (PMID:27484237)
• A2ML1-related otitis media susceptibility may be mediated by changes in the middle ear microbiome. (PMID:27799062)
• Brain gene expression of PADI2, ZNF385A, PSD2, and A2ML1 and DNA methylation dysregulations are implicated in the alteration of brain tissue properties associated with late-life cognitive decline above and beyond the influence of common neuropathologic conditions. (PMID:29084334)
• The functional assessment supported the pathogenicity of the RAF1 and RIT1 variants of unknown significance (VUSs), while the significance of two VUSs in A2ML1 remained unclear. (PMID:29402968)
• Study identified 16 novel A2ML1 variants in otitis media patients, two of which are pathogenic further providing evidence to support a role for A2ML1 in middle ear mucosal pathology. Sequencing of patients salivary RNA samples demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. (PMID:31009165)
• The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered. (PMID:33082526)
• Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family. (PMID:35641520)
• Audiologic Measures in an Indigenous Community with A2ML1- and FUT2-Related Otitis Media. (PMID:36719978)
• A2ML1 Inhibits Esophageal Squamous Cell Carcinoma Progression and Serves as a Novel Prognostic Biomarker. (PMID:37954860)

Cross-species orthologs

19 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:dkey-46g23.5	ENSDARG00000008835
danio_rerio	si:dkey-52d15.3	ENSDARG00000041645
danio_rerio	si:dkey-105h12.2	ENSDARG00000041685
danio_rerio	a2ml	ENSDARG00000056314
danio_rerio	zgc:171426	ENSDARG00000074764
danio_rerio	zgc:165518	ENSDARG00000075737
danio_rerio	zgc:165453	ENSDARG00000078183
danio_rerio	si:ch211-212c13.8	ENSDARG00000078757
danio_rerio	si:ch211-212c13.10	ENSDARG00000093199
danio_rerio	a2ml2	ENSDARG00000097105
		ENSDARG00000100979
danio_rerio	zgc:171445	ENSDARG00000115205
danio_rerio	si:dkey-46g23.2	ENSDARG00000115817
danio_rerio	si:dkey-46g23.3	ENSDARG00000116005
drosophila_melanogaster	Tep4	FBGN0041180
drosophila_melanogaster	Tep3	FBGN0041181
drosophila_melanogaster	Tep2	FBGN0041182
drosophila_melanogaster	Tep1	FBGN0041183
caenorhabditis_elegans	tep-1	WBGENE00013969

Paralogs (8): C5 (ENSG00000106804), C3 (ENSG00000125730), PZP (ENSG00000126838), CD109 (ENSG00000156535), CPAMD8 (ENSG00000160111), A2M (ENSG00000175899), C4B (ENSG00000224389), C4A (ENSG00000244731)

Protein

Protein identifiers

Alpha-2-macroglobulin-like protein 1 — A8K2U0 (reviewed: A8K2U0)

Alternative names: C3 and PZP-like alpha-2-macroglobulin domain-containing protein 9

All UniProt accessions (5): A8K2U0, F5GXP1, F5GYG7, H0YGG5, H0YH14

UniProt curated annotations — full annotation on UniProt →

Function. Is able to inhibit all four classes of proteinases by a unique ’trapping’ mechanism. This protein has a peptide stretch, called the ‘bait region’ which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein which traps the proteinase. The entrapped enzyme remains active against low molecular weight substrates (activity against high molecular weight substrates is greatly reduced). Following cleavage in the bait region a thioester bond is hydrolyzed and mediates the covalent binding of the protein to the proteinase. Displays inhibitory activity against chymotrypsin, papain, thermolysin, subtilisin A and, to a lesser extent, elastase but not trypsin. May play an important role during desquamation by inhibiting extracellular proteases.

Subunit / interactions. Monomer.

Subcellular location. Secreted.

Tissue specificity. In the epidermis, expressed predominantly in the granular layer at the apical edge of keratinocytes (at protein level). Also detected in placenta, testis and thymus but not in epithelia of kidney, lung, small intestine or colon.

Disease relevance. Otitis media (OM) [MIM:166760] An inflammation of the middle ear resulting in earache, fever, hearing disturbance, and vertigo. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the protease inhibitor I39 (alpha-2-macroglobulin) family.

Isoforms (2)

UniProt ID	Names	Canonical?
A8K2U0-1	1	yes
A8K2U0-2	2

RefSeq proteins (2): NP_001269353, NP_653271* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001599	Macroglobln_a2	Domain
IPR002890	MG2	Domain
IPR008930	Terpenoid_cyclase/PrenylTrfase	Homologous_superfamily
IPR009048	A-macroglobulin_rcpt-bd	Domain
IPR011625	A2M_N_BRD	Domain
IPR011626	Alpha-macroglobulin_TED	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR019742	MacrogloblnA2_CS	Conserved_site
IPR036595	A-macroglobulin_rcpt-bd_sf	Homologous_superfamily
IPR040839	MG4	Domain
IPR041555	MG3	Domain
IPR041813	A2M_TED	Domain
IPR047565	Alpha-macroglob_thiol-ester_cl	Conserved_site
IPR050473	A2M/Complement_sys	Family

Pfam: PF00207, PF01835, PF07677, PF07678, PF07703, PF17789, PF17791

UniProt features (178 total): strand 103, helix 23, sequence variant 16, turn 11, disulfide bond 10, glycosylation site 5, sequence conflict 5, signal peptide 1, chain 1, cross-link 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7Q61	ELECTRON MICROSCOPY	2.88
7Q60	ELECTRON MICROSCOPY	3.13
7Q62	ELECTRON MICROSCOPY	3.18
7Q5Z	ELECTRON MICROSCOPY	3.25
7Q1Y	X-RAY DIFFRACTION	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A8K2U0-F1	80.61	0.27

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 (1): 970–973

Disulfide bonds (10): 259–279, 464–557, 589–769, 819–847, 845–881, 919–1307, 1075–1123, 1338–1453, 40–78, 241–291

Glycosylation sites (5): 120, 281, 409, 857, 1020

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 50 (showing top): GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_REGULATION_OF_PEPTIDASE_ACTIVITY, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOBP_REGULATION_OF_PROTEOLYSIS, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_REGULATOR_ACTIVITY, GOMF_SERINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, GOBP_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, LIN_SILENCED_BY_TUMOR_MICROENVIRONMENT, RICKMAN_HEAD_AND_NECK_CANCER_E, BOSCO_EPITHELIAL_DIFFERENTIATION_MODULE, GOMF_ENDOPEPTIDASE_REGULATOR_ACTIVITY, ATF6_TARGET_GENES

GO Biological Process (1): regulation of endopeptidase activity (GO:0052548)

GO Molecular Function (3): serine-type endopeptidase inhibitor activity (GO:0004867), peptidase inhibitor activity (GO:0030414), endopeptidase inhibitor activity (GO:0004866)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), extracellular exosome (GO:0070062), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endopeptidase activity	2
regulation of peptidase activity	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

988 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
A2ML1	CTRB2	Q6GPI1	808
A2ML1	KLK7	P49862	802
A2ML1	CTRB1	P17538	780
A2ML1	KLK6	Q92876	738
A2ML1	PPL	O60437	707
A2ML1	EVPL	Q92817	694
A2ML1	SHOC2	Q9UQ13	640
A2ML1	DSG3	P32926	631
A2ML1	RASA2	Q15283	622
A2ML1	LZTR1	Q8N653	621
A2ML1	DSP	P15924	603
A2ML1	PLEC	Q15149	603
A2ML1	DST	Q03001	596
A2ML1	EPPK1	P58107	574
A2ML1	DSG1	Q02413	568

IntAct

140 interactions, top by confidence:

A	B	Type	Score
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
ZSCAN12	A2ML1	psi-mi:“MI:0914”(association)	0.530
NPPA	A2ML1	psi-mi:“MI:0914”(association)	0.530
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
ZFAND4	A2ML1	psi-mi:“MI:0914”(association)	0.530
FRMD1	A2ML1	psi-mi:“MI:0914”(association)	0.530
GMCL1	A2ML1	psi-mi:“MI:0914”(association)	0.530
UGT1A10	A2ML1	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
GPR148	A2ML1	psi-mi:“MI:0915”(physical association)	0.400
FOXD4	A2ML1	psi-mi:“MI:0914”(association)	0.350
FOXH1	A2ML1	psi-mi:“MI:0914”(association)	0.350
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
ECH1	A2ML1	psi-mi:“MI:0914”(association)	0.350
TOX4	A2ML1	psi-mi:“MI:0914”(association)	0.350
THRA	A2ML1	psi-mi:“MI:0914”(association)	0.350
PI4KA	A2ML1	psi-mi:“MI:0914”(association)	0.350
PDE4DIP	A2ML1	psi-mi:“MI:0914”(association)	0.350
SLC39A11	A2ML1	psi-mi:“MI:0914”(association)	0.350
CCNYL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
CDK15	A2ML1	psi-mi:“MI:0914”(association)	0.350
FCRL5	A2ML1	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0AAQ4VMX2, A6X935, A8K2U0, I2C090, P01023, P01029, P01030, P01031, P06238, P06684, P06756, P08649, P08650, P0C0L4, P0C0L5, P14046, P19069, P19827, P20740, P20742, P24063, P28665, P28666, P43406, P61625, P79263, P80746, P97278, P98093, Q03626, Q06274, Q0VCM5, Q14624, Q29052, Q3T052, Q3UU35, Q5R4N8, Q61702, Q61838, Q63041

Diamond homologs: A8K2U0, P01023, P06238, P14046, P20739, P20740, P20742, P28665, P28666, Q03626, Q3UU35, Q5R4N8, Q61838, Q63041, Q6GQT1, Q6IE52, Q6ZMU1, Q7SIH1, P20738, Q6IE37, Q6YHK3, Q8IZJ3, Q8R422, P23667, Q8YM40, J3S836, P01024, P01025, P01026, P01027, P06684, P08650, P0C0L4, P0C0L5, P12247, P12387, Q2UVX4, Q91132

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1986 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	1027
Likely benign	600
Benign	192

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3244256	NC_000012.11:g.(?7053285)(9027607_?)del	Pathogenic
617555	NM_144670.6(A2ML1):c.10C>T (p.Gln4Ter)	Likely pathogenic

SpliceAI

4648 predictions. Top by Δscore:

Variant	Effect	Δscore
12:8822714:G:GG	donor_gain	1.0000
12:8838321:T:TA	acceptor_gain	1.0000
12:8838326:A:AG	acceptor_gain	1.0000
12:8838327:C:G	acceptor_gain	1.0000
12:8838334:A:AG	acceptor_gain	1.0000
12:8838334:A:C	acceptor_loss	1.0000
12:8838334:AGACT:A	acceptor_gain	1.0000
12:8838335:G:GG	acceptor_gain	1.0000
12:8838335:GAC:G	acceptor_gain	1.0000
12:8838335:GACT:G	acceptor_gain	1.0000
12:8838335:GACTG:G	acceptor_gain	1.0000
12:8838451:GTAA:G	donor_loss	1.0000
12:8838452:T:A	donor_loss	1.0000
12:8839107:CTGCA:C	acceptor_loss	1.0000
12:8839108:TGCAG:T	acceptor_loss	1.0000
12:8839109:GCA:G	acceptor_loss	1.0000
12:8839110:CAGG:C	acceptor_loss	1.0000
12:8839111:A:AG	acceptor_gain	1.0000
12:8839112:G:GA	acceptor_loss	1.0000
12:8839112:G:GG	acceptor_gain	1.0000
12:8839112:GGT:G	acceptor_gain	1.0000
12:8839112:GGTGT:G	acceptor_gain	1.0000
12:8839219:GAAG:G	donor_gain	1.0000
12:8839220:A:T	donor_gain	1.0000
12:8839221:AGGT:A	donor_loss	1.0000
12:8839224:T:G	donor_loss	1.0000
12:8841533:GGAG:G	donor_gain	1.0000
12:8841534:GAGG:G	donor_gain	1.0000
12:8841535:AGGT:A	donor_loss	1.0000
12:8841538:T:A	donor_loss	1.0000

AlphaMissense

9516 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:8851836:T:A	W763R	0.993
12:8851836:T:C	W763R	0.993
12:8851838:G:C	W763C	0.990
12:8851838:G:T	W763C	0.990
12:8829736:G:C	R140P	0.987
12:8847630:T:A	C589S	0.987
12:8847631:G:C	C589S	0.987
12:8847630:T:C	C589R	0.985
12:8851856:C:G	C769W	0.984
12:8851855:G:A	C769Y	0.983
12:8851854:T:C	C769R	0.982
12:8843236:A:C	S451R	0.981
12:8843238:C:A	S451R	0.981
12:8843238:C:G	S451R	0.981
12:8850249:T:A	W737R	0.981
12:8850249:T:C	W737R	0.981
12:8850257:G:C	W739C	0.981
12:8850257:G:T	W739C	0.981
12:8847632:T:G	C589W	0.980
12:8835648:T:C	F209L	0.979
12:8835650:C:A	F209L	0.979
12:8835650:C:G	F209L	0.979
12:8847631:G:A	C589Y	0.978
12:8857557:T:C	F1026L	0.978
12:8857559:T:A	F1026L	0.978
12:8857559:T:G	F1026L	0.978
12:8835609:T:G	Y196D	0.977
12:8847624:T:C	S587P	0.977
12:8863994:T:C	F1235L	0.975
12:8863996:C:A	F1235L	0.975

dbSNP variants (sampled 300 via entrez): RS1000014048 (12:8858349 G>A), RS1000093436 (12:8887243 A>G), RS1000137031 (12:8870613 G>T), RS1000170907 (12:8875850 A>G), RS1000173775 (12:8837646 C>T), RS1000196745 (12:8837966 C>G), RS1000231923 (12:8855649 G>A,C), RS1000265639 (12:8880272 A>G), RS1000305522 (12:8886898 C>T), RS1000375188 (12:8873634 C>T), RS1000388207 (12:8881095 G>A,T), RS1000431199 (12:8873994 G>T), RS1000452274 (12:8826485 G>A), RS1000556588 (12:8867731 G>T), RS1000568185 (12:8826672 G>A,C)

Disease associations

OMIM: gene MIM:610627 | disease phenotypes: MIM:163950, MIM:166760, MIM:202370, MIM:615833, MIM:211900

GenCC curated gene-disease

Disease	Classification	Inheritance
Noonan syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Noonan syndrome	Disputed	AD

Mondo (7): Noonan syndrome (MONDO:0018997), otitis media, susceptibility to (MONDO:0008162), otitis media (MONDO:0005441), peroxisome biogenesis disorder 2B (MONDO:0008736), developmental and epileptic encephalopathy, 21 (MONDO:0014360), Noonan syndrome 1 (MONDO:0008104), tumoral calcinosis, hyperphosphatemic, familial, 1 (MONDO:0100252)

Orphanet (4): Noonan syndrome (Orphanet:648), Neonatal adrenoleukodystrophy (Orphanet:44), Non-specific early-onset epileptic encephalopathy (Orphanet:442835), Familial tumoral calcinosis (Orphanet:53715)

HPO phenotypes

3 total (4 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000403	Recurrent otitis media
HP:0010982	Polygenic inheritance
HP:0000388	Otitis media

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002221_28	Cholesterol, total	2.000000e-09
GCST004235_37	Total cholesterol levels	5.000000e-11
GCST004746_37	Small cell lung carcinoma	3.000000e-06
GCST009391_1943	Metabolite levels	8.000000e-06
GCST010002_207	Refractive error	1.000000e-40
GCST012490_126	Femur bone mineral density x serum urate levels interaction	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0009766	asparagine measurement
EFO:0004531	urate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
D010033	Otitis Media	C09.218.705.663

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases methylation, affects expression, increases expression	3
Benzo(a)pyrene	decreases methylation, decreases expression	2
pyrogallol 1,3-dimethyl ether	increases expression, decreases expression, affects cotreatment, affects localization	1
ethyl-p-hydroxybenzoate	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Allergens	increases expression	1
Furaldehyde	affects cotreatment, affects localization, increases expression	1
Methapyrilene	decreases methylation	1
Nickel	decreases expression	1
Oxygen	increases expression	1
Sodium Chloride	affects cotreatment, increases expression, affects localization, decreases expression	1
Testosterone	decreases expression	1
Aflatoxin B1	decreases methylation	1
Lactic Acid	increases expression	1
Permethrin	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00189462	PHASE4	COMPLETED	A Pilot Study to Evaluate the Efficacy of Montelukast in the Treatment of Acute Otitis Media (AOM) in Children
NCT00393159	PHASE4	UNKNOWN	The Influence of The Ear Popper on Serous Otitis Media and on the Accompanying Conductive Hearing Loss in Children
NCT00419380	PHASE4	COMPLETED	Treatment of Clogged Tympanostomy Tubes: An Off-Label Use of Dornase Alfa (Pulmozyme®)
NCT00539149	PHASE4	COMPLETED	Long-term Antibiotics for Treatment and Prevention of Otitis Media in Aborignal Children
NCT00956748	PHASE4	WITHDRAWN	N-Acetylcysteine as an Adjunct for Refractory Chronic Suppurative Otitis Media
NCT01174849	PHASE4	COMPLETED	Pneumococcal Vaccines Early and in Combination
NCT01244126	PHASE4	COMPLETED	Postoperative Effects of Intranasal Fentanyl, IV and IM Morphine in Children Undergoing Myringotomy
NCT01735084	PHASE4	COMPLETED	Using Pneumococcal Vaccines in Combination for Maximum Protection From Ear and Lung Infections in First 3 Years of Life
NCT02653742	PHASE4	UNKNOWN	Ketorolac Sublingual vs. Fentanyl Intranasal in Pain Control for Bilateral Myringotomy and Tubes (BMT) Placement in Children
NCT03655665	PHASE4	RECRUITING	Does Topical Otic Drop Use at Time of Tympanostomy Tube Surgery Improve Outcomes When no Middle Ear Effusion is Present
NCT04600752	PHASE4	COMPLETED	Study to Evaluate the Safety and Clinical Efficacy of Augmentin® Extra Strength-600 in Children With Acute Otitis Media in India
NCT00452725	PHASE3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	PHASE3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	PHASE3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	PHASE3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	PHASE3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT00000363	PHASE3	COMPLETED	Acute Otitis Media: Adjuvant Therapy to Improve Outcome
NCT00044473	PHASE3	COMPLETED	A Study of the Effectiness and Safety of Levofloxacin in Treating Children With a Rapid and Severe Onset of Infection and Inflammation of the Middle Ear That is Difficult to Treat
NCT00051753	PHASE3	COMPLETED	Levofloxacin In The Treatment Of Children With Recurrent And/or Persistent Acute Otitis Media
NCT00174811	PHASE3	TERMINATED	Comparative Study to Evaluate the Efficacy and Safety of Telithromycin Given Once Daily Versus Cefuroxime Axetil Given Twice Daily in Children With Middle Ear Infections
NCT00360100	PHASE3	COMPLETED	Zmax Pediatric Vs Adult Concentration For The Treatment Of Acute Otitis Media
NCT00378417	PHASE3	COMPLETED	Efficacy Trial of Two Pneumococcal Conjugate Vaccines (PncCRM and PncOMPC) for Prevention of Acute Otitis Media Due to Vaccine Serotypes
NCT00581711	PHASE3	COMPLETED	Improving Otitis Media Care With Clinical Decision Support
NCT00638534	PHASE3	COMPLETED	Japanese Study Evaluating the Effects of Telithromycin in Children With Acute Otitis Media
NCT00781521	PHASE3	COMPLETED	Safety and Efficacy of Floxin Otic Solution in the Treatment of Acute Otitis Media in Children
NCT01619462	PHASE3	UNKNOWN	Safety and Immunogenicity of 10-valent and 13-valent Pneumococcal Conjugate Vaccines in Papua New Guinean Children
NCT02432105	PHASE3	COMPLETED	Safety and Efficacy of EXE844 Otic Suspension in Otitis Media at Time of Tympanostomy Tube Insertion (OMTT)
NCT02436304	PHASE3	COMPLETED	Safety and Efficacy of EXE844 Otic Suspension in Otitis Media at Time of Tympanostomy Tube Insertion (OMTT) - Study 2
NCT02600559	PHASE3	COMPLETED	Open-Label Study of OTO-201 in Pediatric Subjects With a History of Otitis Media Requiring Tympanostomy Tubes
NCT02703389	PHASE3	COMPLETED	Improving Knowledge Translation Upon Emergency Department Discharge
NCT04016051	PHASE3	COMPLETED	Acceptance of Clarithromycin in a Straw Compared to Syrup in Children With Upper Respiratory Tract Infections
NCT07189572	PHASE3	NOT_YET_RECRUITING	Intranasal Corticosteroid Spray for Preventing Otitis Media With Effusion After Radiotherapy in Nasopharyngeal Carcinoma
NCT00351221	PHASE2	TERMINATED	Research Study Using Recombinant Human Insulin-Like Growth Factor-1/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 for Children With Noonan Syndrome
NCT06555237	PHASE2	RECRUITING	MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies
NCT06668805	PHASE2	RECRUITING	A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment
NCT00010465	PHASE2	COMPLETED	Nervous System Manipulation and Botanicals for the Treatment of Recurrent Ear Infections in Children
NCT00219401	PHASE2	COMPLETED	Neonatal Immunization With Pneumococcal Conjugate Vaccine in Papua New Guinea
NCT00276042	PHASE2	COMPLETED	A Trial to Evaluate Faropenem Medoxomil in the Treatment of Acute Otitis Media
NCT01312038	PHASE2	COMPLETED	Effect of Simethicone on Eustachian Tube Dysfunction