ADD3

Summary

ADD3 (adducin 3, HGNC:245) is a protein-coding gene on chromosome 10q25.1-q25.2, encoding Gamma-adducin (Q9UEY8). Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network.

Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma. The three subunits are encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. While adducins alpha and gamma are ubiquitously expressed, the expression of adducin beta is restricted to brain and hematopoietic tissues. Adducin, originally purified from human erythrocytes, was found to be a heterodimer of adducins alpha and beta. Polymorphisms resulting in amino acid substitutions in these two subunits have been associated with the regulation of blood pressure in an animal model of hypertension. Heterodimers consisting of alpha and gamma subunits have also been described. Structurally, each subunit is comprised of two distinct domains. The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Alternatively spliced adducin gamma transcripts encoding different isoforms have been described. The functions of the different isoforms are not known.

Source: NCBI Gene 120 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebral palsy, spastic quadriplegic, 3 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 267 total
• Phenotypes (HPO): 20
• MANE Select transcript: NM_016824

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:245
Approved symbol	ADD3
Name	adducin 3
Location	10q25.1-q25.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000148700
Ensembl biotype	protein_coding
OMIM	601568
Entrez	120

Gene structure

Transcript identifiers

Ensembl transcripts: 90 — 73 protein_coding, 17 protein_coding_CDS_not_defined

ENST00000277900, ENST00000356080, ENST00000360162, ENST00000459738, ENST00000468251, ENST00000468345, ENST00000472568, ENST00000473669, ENST00000475954, ENST00000479805, ENST00000484622, ENST00000486014, ENST00000487085, ENST00000488104, ENST00000488799, ENST00000488837, ENST00000492162, ENST00000495661, ENST00000496517, ENST00000497125, ENST00000901326, ENST00000901327, ENST00000901328, ENST00000901329, ENST00000901330, ENST00000901331, ENST00000901332, ENST00000901333, ENST00000901334, ENST00000901335, ENST00000901336, ENST00000901337, ENST00000901338, ENST00000901339, ENST00000901340, ENST00000901341, ENST00000901342, ENST00000901343, ENST00000901344, ENST00000901345, ENST00000901346, ENST00000901347, ENST00000901348, ENST00000901349, ENST00000901350, ENST00000901351, ENST00000901352, ENST00000901353, ENST00000901354, ENST00000901355, ENST00000901356, ENST00000901357, ENST00000901358, ENST00000901359, ENST00000901360, ENST00000922591, ENST00000922592, ENST00000922593, ENST00000922594, ENST00000922595, ENST00000922596, ENST00000922597, ENST00000922598, ENST00000958043, ENST00000958044, ENST00000958045, ENST00000958046, ENST00000958047, ENST00000958048, ENST00000958049, ENST00000958050, ENST00000958051, ENST00000958052, ENST00000958053, ENST00000958054, ENST00000958055, ENST00000958056, ENST00000958057, ENST00000958058, ENST00000958059, ENST00000958060, ENST00000958061, ENST00000958062, ENST00000958063, ENST00000958064, ENST00000958065, ENST00000958066, ENST00000958067, ENST00000958068, ENST00000958069

RefSeq mRNA: 7 — MANE Select: NM_016824 NM_001121, NM_001320591, NM_001320592, NM_001320593, NM_001320594, NM_016824, NM_019903

CCDS: CCDS7561, CCDS7562

Canonical transcript exons

ENST00000356080 — 15 exons

Exon	Start	End
ENSE00000986799	110118587	110118736
ENSE00000986800	110119211	110119354
ENSE00000986801	110119466	110119564
ENSE00000986802	110122110	110122292
ENSE00000986803	110124017	110124274
ENSE00000986819	110132305	110132400
ENSE00001408307	110133326	110135565
ENSE00001877718	110007984	110008299
ENSE00003498833	110116259	110116410
ENSE00003557770	110126417	110126503
ENSE00003576086	110117342	110117422
ENSE00003622072	110112777	110112915
ENSE00003644600	110125826	110125945
ENSE00003646606	110130363	110130486
ENSE00003676508	110100625	110100848

Expression profiles

Bgee: expression breadth ubiquitous, 303 present calls, max score 99.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 69.5652 / max 609.8504, expressed in 1766 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106937	23.5068	1721
106941	14.9304	1586
106931	12.4857	867
106934	4.2199	808
106943	3.8417	530
106940	2.9613	1236
106939	1.6697	812
106936	1.6219	991
106929	1.3241	551
106933	0.8230	374

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.96	gold quality
oocyte	CL:0000023	99.68	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.45	gold quality
CA1 field of hippocampus	UBERON:0003881	99.45	gold quality
corpus callosum	UBERON:0002336	99.38	gold quality
lateral globus pallidus	UBERON:0002476	99.37	gold quality
corpus epididymis	UBERON:0004359	99.33	gold quality
trigeminal ganglion	UBERON:0001675	99.32	gold quality
pigmented layer of retina	UBERON:0001782	99.21	gold quality
retina	UBERON:0000966	99.20	gold quality
subthalamic nucleus	UBERON:0001906	99.20	gold quality
caput epididymis	UBERON:0004358	99.19	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.18	gold quality
dorsal root ganglion	UBERON:0000044	99.15	gold quality
medulla oblongata	UBERON:0001896	99.13	gold quality
skin of hip	UBERON:0001554	99.12	gold quality
jejunal mucosa	UBERON:0000399	99.10	gold quality
renal glomerulus	UBERON:0000074	99.06	gold quality
olfactory bulb	UBERON:0002264	99.06	gold quality
calcaneal tendon	UBERON:0003701	99.05	gold quality
ventral tegmental area	UBERON:0002691	99.03	gold quality
superior vestibular nucleus	UBERON:0007227	99.03	gold quality
cranial nerve II	UBERON:0000941	99.02	gold quality
kidney epithelium	UBERON:0004819	99.01	gold quality
inferior vagus X ganglion	UBERON:0005363	99.01	gold quality
epididymis	UBERON:0001301	98.99	gold quality
metanephric glomerulus	UBERON:0004736	98.98	gold quality
epithelium of nasopharynx	UBERON:0001951	98.94	gold quality
nasopharynx	UBERON:0001728	98.92	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.86	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	707.22
E-GEOD-135922	yes	47.72
E-HCAD-10	yes	32.92
E-GEOD-125970	yes	18.49
E-CURD-46	yes	12.94
E-MTAB-8410	yes	9.37
E-GEOD-130148	yes	6.11
E-MTAB-5061	no	3.22
E-HCAD-31	no	2.03
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2

miRNA regulators (miRDB)

154 targeting ADD3, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
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-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-539-5P	99.93	70.30	2855

Literature-anchored findings (GeneRIF, showing 25)

• The interaction of ADD1 and ADD3 gene variants in humans is statistically associated with variation in blood pressure, suggesting the presence of epistatic effects among these loci. (PMID:15716695)
• The early expression of ADD3 suggests that it may have a role in erythroblasts but is replaced by ADD2 in later stages of erythropoiesis. (PMID:15963851)
• Left ventricular diastolic relaxation is modulated by genetic variation in ADD3. (PMID:18475162)
• In ADD1 GlyGly homozygotes, the properties of the brachial artery are related to the ADD3 (A386G) polymorphism, but the underlying mechanism needs further clarification. (PMID:18787518)
• These findings suggest novel roles for adducins in stabilization of epithelial junctions and regulation of junctional remodeling. (PMID:20810786)
• gamma-adducin may influence blood pressure homeostasis by modulating renal NaCl transport. (PMID:21164023)
• High expression of ADD3 is associated with glioma. (PMID:23814265)
• Homozygous p.G367D mutation in ADD3 causes spastic diplegic/quadriplegic cerebral palsy and intellectual disability. (PMID:23836506)
• Common genetic variants in 10q24.2 can alter biliary atresia risk by regulating ADD3 expression levels in the liver, and may exert an effect on disease epidemiology and on the general population. (PMID:23872602)
• ADD3 gene may be functionally relevant for the development of biliary atresia (PMID:24104524)
• ADD3 gene plays an important role in biliary atresia pathogenesis. (PMID:25285724)
• ADD3 gene deletion is associated with acute lymphoblastic leukemia. (PMID:28033648)
• MiR-145-5p was confirmed to target ADD3 by luciferase reporter assay. The downregulation of miR-145 may contribute to liver fibrosis in Biliary atresia by upregulating the expression of ADD3. (PMID:28902846)
• ADD3 and ADD3-AS1 variants increased susceptibility to BA, suggesting that these genes may play an additive role in the pathogenesis of the disease. (PMID:29508064)
• The intragenic epistatic association of ADD3 with biliary atresia in Southern Han Chinese population has been reported. (PMID:29685956)
• Data indicate lysine acetyltransferase 2B (KAT2B) as a susceptibility gene for kidney and heart disease in adducin 3 (gamma) protein (ADD3)-associated disorders. (PMID:29768408)
• Loss of cytoskeleton protein ADD3 promotes tumor growth and angiogenesis in glioblastoma multiforme. (PMID:31958485)
• Increased expression of phosphorylated adducin in tumor cells. (PMID:32237935)
• Association of common variation in ADD3 and GPC1 with biliary atresia susceptibility. (PMID:32315284)
• Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis. (PMID:33172155)
• QKI-5 regulates the alternative splicing of cytoskeletal gene ADD3 in lung cancer. (PMID:33196842)
• Posttranscriptional inhibition of gamma-adducin promotes the proliferation and migration of osteosarcoma cells. (PMID:34632867)
• The correlation between rs2501577 gene polymorphism and biliary atresia: a systematic review and meta-analysis. (PMID:37248361)
• Knockdown of long noncoding RNA SAN rejuvenates aged adipose-derived stem cells via miR-143-3p/ADD3 axis. (PMID:37605290)
• Contribution of ADD3 and the HLA Genes to Biliary Atresia Risk in Chinese. (PMID:37834180)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	add3a	ENSDARG00000040874
danio_rerio	add3b	ENSDARG00000056250
mus_musculus	Add3	ENSMUSG00000025026
rattus_norvegicus	Add3	ENSRNOG00000012820
drosophila_melanogaster	hts	FBGN0263391
caenorhabditis_elegans		WBGENE00000073

Paralogs (2): ADD2 (ENSG00000075340), ADD1 (ENSG00000087274)

Protein

Protein identifiers

Gamma-adducin — Q9UEY8 (reviewed: Q9UEY8)

Alternative names: Adducin-like protein 70

All UniProt accessions (2): Q9UEY8, Q5VU08

UniProt curated annotations — full annotation on UniProt →

Function. Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. Plays a role in actin filament capping. Binds to calmodulin. Involved in myogenic reactivity of the renal afferent arteriole (Af-art), renal interlobular arteries and middle cerebral artery (MCA) to increased perfusion pressure. Involved in regulation of potassium channels in the vascular smooth muscle cells (VSMCs) of the Af-art and MCA ex vivo. Involved in regulation of glomerular capillary pressure, glomerular filtration rate (GFR) and glomerular nephrin expression in response to hypertension. Involved in renal blood flow (RBF) autoregulation. Plays a role in podocyte structure and function. Regulates globular monomer actin (G-actin) and filamentous polymer actin (F-actin) ratios in the primary podocytes affecting actin cytoskeleton organization. Regulates expression of synaptopodin, RhoA, Rac1 and CDC42 in the renal cortex and the primary podocytes. Regulates expression of nephrin in the glomeruli and in the primary podocytes, expression of nephrin and podocinin in the renal cortex, and expression of focal adhesion proteins integrin alpha-3 and integrin beta-1 in the glomeruli. Involved in cell migration and cell adhesion of podocytes, and in podocyte foot process effacement. Regulates expression of profibrotics markers MMP2, MMP9, TGF beta-1, tubular tight junction protein E-cadherin, and mesenchymal markers vimentin and alpha-SMA. Promotes the growth of neurites.

Subunit / interactions. Heterodimer of an alpha and a gamma subunit.

Subcellular location. Cytoplasm. Cytoskeleton. Cell membrane.

Tissue specificity. ubiquitously expressed. Cleavage fragment 1-357 is abundantly expressed in the brain of patients with Alzheimer disease (AD), but hardly detectable in age-matched control individuals (at protein level).

Post-translational modifications. Sumoylated. Proteolytically cleaved by asparagine endopeptidase (AEP) into 2 fragments. Overexpression of the 1-357 fragment induces neuronal apoptosis, and overexpression of either 1-357 or 358-706 fragment increases the degeneration of dendritic spines. Overexpression of the 1-357 fragment impairs neurite outgrowth by downregulating the expression of Rac2, and induces synaptic dysfunction and cognitive impairments in tau P301S transgenic mice, a mouse model for Alzheimer disease (AD).

Disease relevance. Cerebral palsy, spastic quadriplegic 3 (CPSQ3) [MIM:617008] A form of cerebral palsy, a group of non-progressive disorders of movement and/or posture resulting from defects in the developing central nervous system. CPSQ3 is an autosomal recessive neurodevelopmental disorder characterized by variable spasticity and cognitive impairment. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Comprised of three regions: a N-terminal protease-resistant globular head region, a short connecting subdomain, and a protease-sensitive tail region.

Similarity. Belongs to the aldolase class II family. Adducin subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UEY8-1	2, Long	yes
Q9UEY8-2	1, Short

RefSeq proteins (7): NP_001112, NP_001307520, NP_001307521, NP_001307522, NP_001307523, NP_058432, NP_063968 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001303	Aldolase_II/adducin_N	Domain
IPR036409	Aldolase_II/adducin_N_sf	Homologous_superfamily
IPR051017	Aldolase-II_Adducin_sf	Family

Pfam: PF00596

UniProt features (37 total): modified residue 15, sequence conflict 7, region of interest 6, compositionally biased region 3, initiator methionine 1, chain 1, site 1, cross-link 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UEY8-F1	66.83	0.23

Functional residue map

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

Catalytic / active sites (1): 357 (cleavage by asparagine endopeptidase (aep))

Post-translational modifications (16): 2, 42, 64, 402, 414, 423, 442, 461, 585, 590, 673, 677, 679, 681, 683, 484

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-5223345	Miscellaneous transport and binding events
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9035034	RHOF GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-382551	Transport of small molecules
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 562 (showing top): GCACCTT_MIR18A_MIR18B, RNGTGGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, DORSAM_HOXA9_TARGETS_UP, GOBP_CIRCULATORY_SYSTEM_PROCESS, CMYB_01, CHUNG_BLISTER_CYTOTOXICITY_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_BARBED_END_ACTIN_FILAMENT_CAPPING, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_DEPOLYMERIZATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION

GO Biological Process (5): response to xenobiotic stimulus (GO:0009410), positive regulation of vasoconstriction (GO:0045907), barbed-end actin filament capping (GO:0051016), positive regulation of cytoskeleton organization (GO:0051495), cytoskeleton organization (GO:0007010)

GO Molecular Function (5): protein kinase C binding (GO:0005080), structural constituent of cytoskeleton (GO:0005200), calmodulin binding (GO:0005516), actin filament binding (GO:0051015), actin binding (GO:0003779)

GO Cellular Component (10): condensed nuclear chromosome (GO:0000794), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), brush border (GO:0005903), cell-cell junction (GO:0005911), cell cortex (GO:0005938), postsynaptic density (GO:0014069), membrane (GO:0016020), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
RHO GTPase cycle	2
Transport of small molecules	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoskeleton organization	2
cytoplasm	2
cell periphery	2
response to chemical	1
regulation of vasoconstriction	1
vasoconstriction	1
positive regulation of multicellular organismal process	1
actin filament capping	1
positive regulation of organelle organization	1
regulation of cytoskeleton organization	1
organelle organization	1
protein kinase binding	1
structural molecule activity	1
cytoskeleton	1
protein binding	1
actin binding	1
protein-containing complex binding	1
cytoskeletal protein binding	1
nuclear chromosome	1
condensed chromosome	1
nucleus	1
intracellular membraneless organelle	1
membrane	1
microvillus	1
apical part of cell	1
cluster of actin-based cell projections	1
anchoring junction	1
asymmetric synapse	1
postsynaptic specialization	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1610 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADD3	EPB41	P11171	993
ADD3	DMTN	Q08495	987
ADD3	ANK2	Q01484	986
ADD3	ANK1	P16157	984
ADD3	ANK3	Q12955	978
ADD3	TMOD4	Q9NZQ9	947
ADD3	TMOD1	P28289	939
ADD3	TMOD3	Q9NYL9	939
ADD3	TMOD2	Q9NZR1	937
ADD3	CALML6	Q8TD86	912
ADD3	CALML4	Q96GE6	912
ADD3	CALML3	P27482	911
ADD3	CALML5	Q9NZT1	911
ADD3	GYPC	P04921	886
ADD3	CALM1	P02593	880

IntAct

91 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ADD2	ADD1	psi-mi:“MI:0914”(association)	0.560
MED13L	MED14	psi-mi:“MI:0914”(association)	0.530
ANKRD29	ADD1	psi-mi:“MI:0914”(association)	0.530
CUL3	ACOT7	psi-mi:“MI:0914”(association)	0.500
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
FAM78A	ADD3	psi-mi:“MI:0915”(physical association)	0.400
ADD3	AGTR1	psi-mi:“MI:0915”(physical association)	0.370
ADD3	OPRM1	psi-mi:“MI:0915”(physical association)	0.370
ATXN1	ADD3	psi-mi:“MI:0915”(physical association)	0.370
HSPB1	ADD3	psi-mi:“MI:0915”(physical association)	0.370
ADD3	HSPB1	psi-mi:“MI:0915”(physical association)	0.370
HTT	ADD3	psi-mi:“MI:0915”(physical association)	0.370
MYO19	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
STAT5A	R3HDM2	psi-mi:“MI:0914”(association)	0.350
Lima1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Calml3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Tmod3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
SYNPO	LMO7	psi-mi:“MI:0914”(association)	0.350
MAPRE1	CTNNB1	psi-mi:“MI:0914”(association)	0.350
Myh9	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CAPZA2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
BCAR1	ARHGEF11	psi-mi:“MI:0914”(association)	0.350
BCAR1	CEP290	psi-mi:“MI:0914”(association)	0.350
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
CCDC61	EPB41L2	psi-mi:“MI:0914”(association)	0.350

BioGRID (181): ADD3 (Affinity Capture-MS), ADD3 (Biochemical Activity), ADD3 (Affinity Capture-MS), ADD3 (Affinity Capture-MS), ADD3 (Affinity Capture-MS), ADD3 (Affinity Capture-MS), ADD3 (Affinity Capture-MS), ADD3 (Two-hybrid), ADD3 (Co-fractionation), ADD3 (Co-fractionation), ADD3 (Proximity Label-MS), ADD3 (Proximity Label-MS), ADD3 (Affinity Capture-MS), ADD3 (Affinity Capture-MS), ADD3 (Affinity Capture-MS)

ESM2 similar proteins: A0JPA1, A4GG66, A4GVD1, A4IG66, A7YWH9, A9L8T6, B0VX73, B1MT31, F1NVK6, G5EBQ8, P18861, P28228, P28229, P36383, P91682, Q00M95, Q0IHQ3, Q0P5V9, Q11186, Q16625, Q28269, Q2HJ66, Q3UZP0, Q499S9, Q5BKX6, Q5RFS5, Q5YLM1, Q61146, Q62847, Q66IE4, Q6GMF8, Q6NZH5, Q6P6T5, Q6PIX5, Q6PJF5, Q6PYT3, Q6R4A8, Q6WQJ1, Q7TMB7, Q7ZXS7

Diamond homologs: A4FWY9, A6UPI8, A6UTG8, A6VGC7, B3S866, B4GY79, B4JLL3, B4L8M2, B4M1W5, F8D9F5, P44777, Q0KBC9, Q29HV4, Q57199, Q58813, Q5FW37, Q5ZLP2, Q62847, Q66I75, Q6CZ24, Q6LY06, Q6NU29, Q9QYB5, Q9UEY8, Q9WVQ5, P35611, P35612, Q02645, Q05764, Q20952, Q5R5V7, Q5RA10, Q63028, Q7LKY2, Q8GHB1, Q9A8Z4, Q9HYH5, Q9L9F0, Q9QYB8, Q9QYC0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKCA	“down-regulates quantity by destabilization”	ADD3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 112 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Downstream signal transduction	5	24.4×	2e-04
VEGFA-VEGFR2 Pathway	6	10.7×	7e-04
RHOA GTPase cycle	6	5.7×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
outflow tract morphogenesis	5	16.3×	5e-03
cellular response to cAMP	5	15.4×	5e-03
actin cytoskeleton organization	8	6.7×	6e-03
positive regulation of gene expression	12	5.0×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	165
Likely benign	72
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

3551 predictions. Top by Δscore:

Variant	Effect	Δscore
10:110100615:A:AG	acceptor_gain	1.0000
10:110100618:A:AG	acceptor_gain	1.0000
10:110100620:TGCA:T	acceptor_loss	1.0000
10:110100621:GCAG:G	acceptor_loss	1.0000
10:110100622:CAG:C	acceptor_loss	1.0000
10:110100623:A:AG	acceptor_gain	1.0000
10:110100624:G:GA	acceptor_gain	1.0000
10:110100624:GAT:G	acceptor_gain	1.0000
10:110100844:GTCCT:G	donor_gain	1.0000
10:110100845:TCCT:T	donor_gain	1.0000
10:110100846:CCT:C	donor_gain	1.0000
10:110100848:TGT:T	donor_loss	1.0000
10:110100849:G:GG	donor_gain	1.0000
10:110100849:GTGAG:G	donor_loss	1.0000
10:110100853:G:C	donor_loss	1.0000
10:110112771:TTACA:T	acceptor_loss	1.0000
10:110112772:TACAG:T	acceptor_loss	1.0000
10:110112774:CAGG:C	acceptor_loss	1.0000
10:110112775:A:AG	acceptor_gain	1.0000
10:110112775:AGGC:A	acceptor_loss	1.0000
10:110112776:G:A	acceptor_loss	1.0000
10:110112776:G:GG	acceptor_gain	1.0000
10:110112916:G:GG	donor_gain	1.0000
10:110112920:G:GG	donor_gain	1.0000
10:110112925:T:G	donor_gain	1.0000
10:110116411:G:GG	donor_gain	1.0000
10:110118696:T:G	donor_gain	1.0000
10:110118734:GCT:G	donor_gain	1.0000
10:110118737:G:GG	donor_gain	1.0000
10:110124013:TTAG:T	acceptor_loss	1.0000

AlphaMissense

4653 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:110124188:T:A	W439R	1.000
10:110124188:T:C	W439R	1.000
10:110124190:G:C	W439C	1.000
10:110124190:G:T	W439C	1.000
10:110125895:T:C	F491L	1.000
10:110125897:T:A	F491L	1.000
10:110125897:T:G	F491L	1.000
10:110133577:T:C	F694L	1.000
10:110133579:T:A	F694L	1.000
10:110133579:T:G	F694L	1.000
10:110112780:T:C	F67L	0.999
10:110112781:T:C	F67S	0.999
10:110112782:T:A	F67L	0.999
10:110112782:T:G	F67L	0.999
10:110112793:T:C	L71S	0.999
10:110118687:G:C	R223P	0.999
10:110122282:T:C	L378P	0.999
10:110125826:T:A	W468R	0.999
10:110125826:T:C	W468R	0.999
10:110125828:G:C	W468C	0.999
10:110125828:G:T	W468C	0.999
10:110125896:T:C	F491S	0.999
10:110125896:T:G	F491C	0.999
10:110125899:T:A	V492D	0.999
10:110126421:G:C	R509P	0.999
10:110133562:T:C	F689L	0.999
10:110133563:T:C	F689S	0.999
10:110133564:C:A	F689L	0.999
10:110133564:C:G	F689L	0.999
10:110133565:C:A	R690S	0.999

dbSNP variants (sampled 300 via entrez): RS1000004262 (10:110041785 C>A,G,T), RS1000009251 (10:110081464 C>T), RS1000029788 (10:110041185 A>T), RS1000072898 (10:110035069 A>G), RS1000084610 (10:110068708 T>A,C), RS1000089165 (10:109996711 G>A,T), RS1000092340 (10:110087068 C>T), RS1000110625 (10:110127708 C>G), RS1000145992 (10:110081842 C>A), RS1000157987 (10:110122774 A>C), RS1000162666 (10:110105927 A>G,T), RS1000166058 (10:110047461 C>G), RS1000273332 (10:110058571 C>T), RS1000291913 (10:110024228 C>G,T), RS1000340786 (10:110032056 A>C,G)

Disease associations

OMIM: gene MIM:601568 | disease phenotypes: MIM:617008

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebral palsy, spastic quadriplegic, 3	Strong	Autosomal recessive
spastic quadriplegic cerebral palsy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder with motor features	Moderate	AR

Mondo (5): cerebral palsy, spastic quadriplegic, 3 (MONDO:0014862), cerebral palsy (MONDO:0006497), complex neurodevelopmental disorder with motor features (MONDO:0100516), microcephaly (MONDO:0001149), spastic quadriplegic cerebral palsy (MONDO:0016215)

Orphanet (1): Inherited congenital spastic tetraplegia (Orphanet:210141)

HPO phenotypes

20 total (21 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000486	Strabismus
HP:0000577	Exotropia
HP:0000605	Supranuclear gaze palsy
HP:0000639	Nystagmus
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001264	Spastic diplegia
HP:0002015	Dysphagia
HP:0002282	Gray matter heterotopia
HP:0002510	Spastic tetraplegia
HP:0003593	Infantile onset
HP:0003828	Variable expressivity
HP:0007256	Abnormal pyramidal sign
HP:0025711	Convergence-retraction nystagmus
HP:0100543	Cognitive impairment
HP:0100021	Cerebral palsy

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000681_1	Biliary atresia	7.000000e-09
GCST003962_6	Bipolar disorder	3.000000e-08
GCST005973_10	White blood cell count	7.000000e-10
GCST005974_8	Neutrophil count	4.000000e-08
GCST008103_19	Bipolar disorder	1.000000e-08
GCST009391_1100	Metabolite levels	5.000000e-06
GCST009391_225	Metabolite levels	4.000000e-06
GCST009391_984	Metabolite levels	7.000000e-07
GCST009391_989	Metabolite levels	3.000000e-06
GCST010002_224	Refractive error	2.000000e-14
GCST010302_8	Cutaneous melanoma or hair colour	3.000000e-11
GCST011102_12	Bipolar disorder	2.000000e-09
GCST012465_25	Bipolar disorder	2.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0010447	3-hydroxyanthranilic acid measurement
EFO:0010491	glycocholate measurement
EFO:0010475	deoxycholate measurement
EFO:0003924	hair color

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

71 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	affects cotreatment, decreases expression, increases expression	6
Benzo(a)pyrene	decreases expression, increases expression, increases methylation, affects methylation	5
bisphenol A	increases expression, affects cotreatment, decreases methylation	4
Air Pollutants	decreases expression, affects expression, increases abundance	4
sodium arsenite	increases abundance, affects cotreatment, decreases expression	3
Estradiol	decreases expression, increases expression	3
Valproic Acid	increases expression, affects expression, increases methylation, affects reaction	3
Cyclosporine	decreases expression	3
Cisplatin	affects cotreatment, increases expression	2
Dexamethasone	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
methylselenic acid	increases expression	1
sodium arsenate	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
cobaltous chloride	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cupric chloride	decreases expression	1
nickel sulfate	decreases expression	1
coumarin	decreases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects cotreatment	1
beta-methylcholine	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	PHASE3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	PHASE3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	PHASE3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01249417	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	PHASE3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01492608	PHASE3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity
NCT01603628	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
NCT01603641	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Lower Limb Spasticity
NCT01633736	PHASE3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
NCT01898520	PHASE3	COMPLETED	A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years
NCT01929434	PHASE3	COMPLETED	Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Patients With Cerebral Paralysis
NCT02002884	PHASE3	COMPLETED	Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02839785	PHASE3	TERMINATED	Analgesia and Physiotherapy in Children With Cerebral Palsy (ANTALKINECP)
NCT03110341	PHASE3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
NCT03302871	PHASE3	COMPLETED	Integrated Management Enhances Functional Gains in Children With Cerebral Palsy Treated by BoNT-A
NCT03306212	PHASE3	COMPLETED	Efficacy of Intermittent Serial Casting on Spastic Wrist Flexion Deformity