ADD1

Summary

ADD1 (adducin 1, HGNC:243) is a protein-coding gene on chromosome 4p16.3, encoding Alpha-adducin (P35611). Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network.

Adducins are a family of cytoskeletal proteins encoded by three genes (alpha, beta, and gamma). Adducin acts as a heterodimer of the related alpha, beta, or gamma subunits. The protein encoded by this gene represents the alpha subunit. Alpha- and beta-adducin include a protease-resistant N-terminal region and a protease-sensitive, hydrophilic C-terminal region. Adducin binds with high affinity to Ca(2+)/calmodulin and is a substrate for protein kinases A and C.

Source: NCBI Gene 118 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 179 total — 42 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 4
• MANE Select transcript: NM_001354761

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:243
Approved symbol	ADD1
Name	adducin 1
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000087274
Ensembl biotype	protein_coding
OMIM	102680
Entrez	118

Gene structure

Transcript identifiers

Ensembl transcripts: 60 — 45 protein_coding, 11 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000264758, ENST00000355842, ENST00000374281, ENST00000398123, ENST00000398125, ENST00000398129, ENST00000503062, ENST00000503169, ENST00000503455, ENST00000506157, ENST00000508277, ENST00000508684, ENST00000509039, ENST00000510101, ENST00000511797, ENST00000513328, ENST00000513762, ENST00000514940, ENST00000534870, ENST00000536078, ENST00000536424, ENST00000538860, ENST00000539108, ENST00000539149, ENST00000540541, ENST00000541051, ENST00000541843, ENST00000651918, ENST00000683351, ENST00000857014, ENST00000857015, ENST00000857016, ENST00000857017, ENST00000857018, ENST00000857019, ENST00000857020, ENST00000857021, ENST00000857022, ENST00000857023, ENST00000857024, ENST00000857025, ENST00000857026, ENST00000857027, ENST00000857028, ENST00000857029, ENST00000922760, ENST00000922761, ENST00000922762, ENST00000948354, ENST00000948355, ENST00000948356, ENST00000948357, ENST00000948358, ENST00000948359, ENST00000948360, ENST00000948361, ENST00000948362, ENST00000948363, ENST00000948364, ENST00000948365

RefSeq mRNA: 13 — MANE Select: NM_001354761 NM_001119, NM_001286645, NM_001354754, NM_001354755, NM_001354756, NM_001354757, NM_001354758, NM_001354759, NM_001354761, NM_001354762, NM_014189, NM_014190, NM_176801

CCDS: CCDS3363, CCDS3364, CCDS43205, CCDS75094, CCDS93468, CCDS93469

Canonical transcript exons

ENST00000683351 — 16 exons

Exon	Start	End
ENSE00000854895	2904764	2905108
ENSE00000854898	2909339	2909431
ENSE00003469278	2881898	2882060
ENSE00003473521	2894013	2894093
ENSE00003475370	2908515	2908604
ENSE00003487286	2926014	2926112
ENSE00003551500	2914884	2915040
ENSE00003551557	2894582	2894731
ENSE00003603942	2875896	2876110
ENSE00003653856	2899259	2899435
ENSE00003656034	2898433	2898531
ENSE00003664578	2884515	2884666
ENSE00003668117	2898184	2898327
ENSE00003741761	2907743	2907844
ENSE00003916033	2928171	2930062
ENSE00003920242	2843844	2844024

Expression profiles

Bgee: expression breadth ubiquitous, 304 present calls, max score 99.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.8811 / max 531.0837, expressed in 1822 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46650	37.1922	1821
46651	10.6570	1739
46653	1.5730	233
46656	0.1748	32
203089	0.0637	13
203088	0.0602	33
46652	0.0527	33
46655	0.0364	10
46661	0.0351	13
46654	0.0134	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.15	gold quality
nerve	UBERON:0001021	99.08	gold quality
tibial nerve	UBERON:0001323	99.08	gold quality
cerebellar hemisphere	UBERON:0002245	99.08	gold quality
cerebellar cortex	UBERON:0002129	99.07	gold quality
right frontal lobe	UBERON:0002810	99.07	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.92	gold quality
body of uterus	UBERON:0009853	98.91	gold quality
lower esophagus	UBERON:0013473	98.91	gold quality
right ovary	UBERON:0002118	98.90	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.89	gold quality
left ovary	UBERON:0002119	98.88	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.87	gold quality
metanephros cortex	UBERON:0010533	98.86	gold quality
putamen	UBERON:0001874	98.83	gold quality
sural nerve	UBERON:0015488	98.83	gold quality
caudate nucleus	UBERON:0001873	98.82	gold quality
right lung	UBERON:0002167	98.82	gold quality
cerebellum	UBERON:0002037	98.81	gold quality
apex of heart	UBERON:0002098	98.79	gold quality
ventricular zone	UBERON:0003053	98.76	gold quality
prefrontal cortex	UBERON:0000451	98.74	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.74	gold quality
amygdala	UBERON:0001876	98.73	gold quality
nucleus accumbens	UBERON:0001882	98.73	gold quality
popliteal artery	UBERON:0002250	98.71	gold quality
tibial artery	UBERON:0007610	98.71	gold quality
adenohypophysis	UBERON:0002196	98.70	gold quality
aorta	UBERON:0000947	98.67	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.67	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	1559.37
E-GEOD-135922	yes	42.20
E-MTAB-7316	yes	37.60
E-ANND-3	yes	15.09

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ID1, TFAP2A

miRNA regulators (miRDB)

68 targeting ADD1, 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-4713-3P	100.00	65.92	505
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4472	99.56	66.08	1478

Literature-anchored findings (GeneRIF, showing 40)

• Role of the alpha-adducin genotype on renal disease progression. (PMID:11918733)
• interaction between diuretic therapy and the adducin variant on the incidence of myocardial infarction and stroke (PMID:11926892)
• ADD1 460W allele associated with cardiovascular disease in hypertensive individuals (PMID:12052841)
• Blood pressure in patients with primary aldosteronism is influenced by alpha-adducin gene polymorphisms. (PMID:12107246)
• Carotid and femoral intima-media thickness were assessed in subjects genotyped for the presence of the ACE D, aldosterone synthase -344T and alpha-adducin 460Trp alleles. (PMID:12172317)
• Patients homozygous for the allele of that polymorphism had a LV mass index significantly higher compared with heterozygotes or homozygotes. These subjects also have significantly lower plasma renin activity. (PMID:12195118)
• The Gly460Trp polymorphism of ADD-1 is associated with low renin hypertension. (PMID:12195119)
• inhibition of the renin-aldosterone system in men and absence of such a compensatory mechanism in women may explain, at least to some extent, the sexual dimorphism of the blood pressure phenotype in relation to the C1797T beta-adducin polymorphism. (PMID:12427140)
• The ACE and alpha-adducin polymorphisms do not play a significant role in the progression of autosomal dominant polycystic kidney to end stage renal failure (PMID:12697976)
• In the series of ADPKD patients no effects was found of the ACE(I/D) polymorphism on the age at ESRD. (PMID:13679477)
• positive association between the alpha-adducin G460W polymorphism and essential hypertension in a northern Chinese population (PMID:14508192)
• In healthy Venezuelan normotensive adults, there is no association between the alpha-adducin 460Trp mutation (G/T), and the state of salt sensitivity or the level of blood pressure. (PMID:14643575)
• the ADD1/ G460W polymorphism was associated with hypertension in female subjects. (PMID:15055253)
• The ACE I/D, alpha-adducin Gly460Trp and aldosterone synthase -344C/T polymorphisms interact to influence systolic blood pressure in Chinese, suggesting that these genes might indeed predispose to hypertension (PMID:15097233)
• The alpha-adducin WW genotype was associated with higher systolic BP among men with a higher sodium intake. (PMID:15110895)
• The present study shows that the Trp460Trp genotype of the alpha-adducin gene is significantly associated with reduced renal plasma flow and glomerular filtration rate. (PMID:15326084)
• Renal function in relation to ADD1 was studied in a Han population. (PMID:15378162)
• 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)
• interaction effect of alpha-adducin Gly460Trp and ACE I/D polymorphisms might play a significant role in regulating baseline BP but not BP response to Benazepril. (PMID:15773232)
• These results suggest that Rho-kinase regulates the association of alpha-adducin and spectrin with the actin cytoskeleton in platelet activation. (PMID:15910744)
• Alpha-adducin Gly460Trp polymorphism, in combination with systolic blood pressure, is a strong predictor of cardiovascular mortality and morbidity. (PMID:16043664)
• In the JingNing population, the adducin 460Trp allele was associated with lower levels of central systolic pressure and pulse pressure. (PMID:16080807)
• The alpha-adducin G614T polymorphism is associated with the antihypertensive effect of hydrochlorothiazide. (PMID:16266470)
• The binding of alpha Adducin to RFX-I and their nuclear co-localization suggests that Adducin can have a role in modulating the transcriptional regulating activity of RFX-I. (PMID:16289097)
• The 460Trp allele of ADD1 contributes substantially to increase carotid artery intima-media thickness, in a male hormonal milieu only, at least in the young age range. (PMID:16531798)
• ADD1 and ACE polymorphisms in hypertension have a joint influence on albuminuria. (PMID:16612256)
• The alpha-adducin G460W polymorphism and the angiotensinogen M235T polymorphism did not modify the difference in blood pressure levels among subjects who used diuretics, beta-blockers, calcium antagonists, or ACE inhibitors. (PMID:16724011)
• ADD1 gene contributes to risk of hypertension & increases mean common carotid IMT in patients with NIDDM. Study indicates that ADD1 polymorphism could be useful in identifying hypertensive NIDDM patients with high risk of mortality. (PMID:17003363)
• ADD1 polymorphism did not influence the effect of low-ceiling diuretics on the risk of myocardial infarction/stroke. (PMID:17189961)
• The angiotensin-converting enzyme (ACE) I/D and the alpha-adducin (ADD1) Gly460Trp polymorphisms are associated with cardiovascular risk factors. (PMID:17452507)
• major finding of the present study was that the a-adducin Gly460Trp polymorphism interacted with exercise intensity to alter the systolic blood pressure response to acute dynamic exercise (PMID:17472579)
• data suggest that the adducin-1 G460W polymorphism influences blood pressure when body mass in and sex are taken into account (PMID:17765140)
• in essential hypertensives the 460Trp allele of ADD1 is strongly associated with an impaired endothelium-dependent vasodilation, a powerful predictor of cardiovascular risk. (PMID:17921817)
• The ADD1 Gly460Trp polymorphism is significantly associated with an increased risk of coronary artery disease as well as blood pressure, indicating that ADD1 plays a role in the pathogenesis of coronary artery disease as well as hypertension. (PMID:17984662)
• Adducin acting through spectrin provides a novel mechanism to regulate global properties of the lateral membrane of bronchial epithelial cells. (PMID:18003973)
• Data show that the alpha-adducin gene TT and ACE II genotypes might be genetic susceptibility factors to hypertension accompanying renal injury. (PMID:18393230)
• patients with ADD1 Trp alleles are sensitive to salt and tubular Na reabsorption remains elevated after volume expansion (PMID:18398333)
• prospective study in a population based cohort of Dutch women strongly suggest that presence of the alpha-adducin Gly460Trp polymorphism increases the risk of stroke (PMID:18458162)
• Left ventricular diastolic relaxation is modulated by genetic variation in ADD1. (PMID:18475162)
• The constitutive reduction of the Na/K pump endocytic rate induced by mutated adducin variants may be relevant in Na-dependent hypertension. (PMID:18524856)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	add1	ENSDARG00000103962
mus_musculus	Add1	ENSMUSG00000029106
rattus_norvegicus	Add1	ENSRNOG00000013039
drosophila_melanogaster	hts	FBGN0263391
caenorhabditis_elegans		WBGENE00000073

Paralogs (2): ADD2 (ENSG00000075340), ADD3 (ENSG00000148700)

Protein

Protein identifiers

Alpha-adducin — P35611 (reviewed: P35611)

Alternative names: Erythrocyte adducin subunit alpha

All UniProt accessions (10): P35611, A0A804HL01, D6RAH3, D6RF25, D6RJE2, E7ENY0, E7EV99, H0Y9H2, H0YFD8, H0YG19

UniProt curated annotations — full annotation on UniProt →

Function. Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. Binds to calmodulin.

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

Subcellular location. Cytoplasm. Cytoskeleton. Cell membrane.

Tissue specificity. Expressed in all tissues. Found in much higher levels in reticulocytes than the beta subunit.

Domain organisation. Each subunit is comprised of three regions: a NH2-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 (6)

UniProt ID	Names	Canonical?
P35611-1	1	yes
P35611-2	2
P35611-3	3
P35611-4	4
P35611-5	5
P35611-6	6

RefSeq proteins (13): NP_001110, NP_001273574, NP_001341683, NP_001341684, NP_001341685, NP_001341686, NP_001341687, NP_001341688, NP_001341690, NP_001341691, NP_054908, NP_054909, NP_789771 (=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 (54 total): modified residue 30, splice variant 6, sequence variant 6, region of interest 4, compositionally biased region 4, mutagenesis site 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35611-F1	65.73	0.29

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 (30): 12, 59, 64, 331, 334, 353, 355, 358, 366, 408, 427, 429, 431, 436, 445, 464, 465, 480, 481, 586 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
445	abolishes phosphorylation by rock2; when associated with d-480.
480	abolishes phosphorylation by rock2; when associated with d-445.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-264870	Caspase-mediated cleavage of cytoskeletal proteins
R-HSA-381038	XBP1(S) activates chaperone genes
R-HSA-5223345	Miscellaneous transport and binding events
R-HSA-109581	Apoptosis
R-HSA-111465	Apoptotic cleavage of cellular proteins
R-HSA-2262752	Cellular responses to stress
R-HSA-381070	IRE1alpha activates chaperones
R-HSA-381119	Unfolded Protein Response (UPR)
R-HSA-382551	Transport of small molecules
R-HSA-5357801	Programmed Cell Death
R-HSA-75153	Apoptotic execution phase
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 336 (showing top): GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_EPITHELIAL_CELL_DEVELOPMENT, TTTGTAG_MIR520D, MORF_SNRP70, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_BARBED_END_ACTIN_FILAMENT_CAPPING, GOBP_REGULATION_OF_ENDOTHELIAL_CELL_DIFFERENTIATION, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_DEPOLYMERIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (18): actin cytoskeleton organization (GO:0030036), barbed-end actin filament capping (GO:0051016), actin filament bundle assembly (GO:0051017), cellular response to calcium ion (GO:0071277), positive regulation of establishment of endothelial barrier (GO:1903142), positive regulation of adherens junction organization (GO:1903393), cell morphogenesis (GO:0000902), in utero embryonic development (GO:0001701), cell volume homeostasis (GO:0006884), cytoskeleton organization (GO:0007010), hemoglobin metabolic process (GO:0020027), erythrocyte differentiation (GO:0030218), regulation of cellular component size (GO:0032535), multicellular organism growth (GO:0035264), homeostasis of number of cells within a tissue (GO:0048873), positive regulation of developmental process (GO:0051094), positive regulation of cellular component organization (GO:0051130), regulation of multicellular organismal development (GO:2000026)

GO Molecular Function (13): RNA binding (GO:0003723), actin binding (GO:0003779), calmodulin binding (GO:0005516), cytoskeletal adaptor activity (GO:0008093), spectrin binding (GO:0030507), protein homodimerization activity (GO:0042803), cadherin binding (GO:0045296), protein heterodimerization activity (GO:0046982), protein dimerization activity (GO:0046983), actin filament binding (GO:0051015), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), structural constituent of cytoskeleton (GO:0005200), protein binding (GO:0005515)

GO Cellular Component (14): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), adherens junction (GO:0005912), focal adhesion (GO:0005925), F-actin capping protein complex (GO:0008290), postsynaptic density (GO:0014069), nuclear body (GO:0016604), membrane (GO:0016020), cell junction (GO:0030054), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Apoptotic cleavage of cellular proteins	1
IRE1alpha activates chaperones	1
Transport of small molecules	1
Programmed Cell Death	1
Apoptotic execution phase	1
Cellular responses to stimuli	1
Unfolded Protein Response (UPR)	1
Cellular responses to stress	1
Apoptosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoskeletal protein binding	3
cytoskeleton organization	2
cellular component organization	2
regulation of developmental process	2
protein binding	2
protein-containing complex binding	2
protein dimerization activity	2
intracellular membraneless organelle	2
actin filament-based process	1
actin filament capping	1
cellular component assembly	1
actin filament bundle organization	1
response to calcium ion	1
cellular response to metal ion	1
establishment of endothelial barrier	1
positive regulation of endothelial cell development	1
regulation of establishment of endothelial barrier	1
adherens junction organization	1
positive regulation of cellular component organization	1
regulation of adherens junction organization	1
anatomical structure morphogenesis	1
chordate embryonic development	1
regulation of cell size	1
cellular homeostasis	1
organelle organization	1
protein metabolic process	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
regulation of anatomical structure size	1
multicellular organismal process	1
developmental growth	1
tissue homeostasis	1
homeostasis of number of cells	1
developmental process	1
positive regulation of biological process	1
positive regulation of cellular process	1
regulation of cellular component organization	1
multicellular organism development	1
regulation of multicellular organismal process	1

Protein interactions and networks

STRING

1822 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADD1	EPB41	P11171	994
ADD1	ANK2	Q01484	988
ADD1	ANK1	P16157	986
ADD1	DMTN	Q08495	986
ADD1	ANK3	Q12955	983
ADD1	TMOD4	Q9NZQ9	970
ADD1	TMOD2	Q9NZR1	956
ADD1	TMOD1	P28289	956
ADD1	TMOD3	Q9NYL9	955
ADD1	GYPC	P04921	894
ADD1	CALML6	Q8TD86	840
ADD1	CALML4	Q96GE6	840
ADD1	CALML5	Q9NZT1	840
ADD1	CALML3	P27482	839
ADD1	ACE	P12821	799

IntAct

103 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CRYAA	ADD1	psi-mi:“MI:0915”(physical association)	0.560
PAK1	ADD1	psi-mi:“MI:0915”(physical association)	0.560
ADD2	ADD1	psi-mi:“MI:0914”(association)	0.560
ADD1	ADD2	psi-mi:“MI:0915”(physical association)	0.560
ADD1	RFX1	psi-mi:“MI:0915”(physical association)	0.540
RFX1	ADD1	psi-mi:“MI:0403”(colocalization)	0.540
MED13L	MED14	psi-mi:“MI:0914”(association)	0.530
DPPA4	ALOX12B	psi-mi:“MI:0914”(association)	0.530
ANKRD29	ADD1	psi-mi:“MI:0914”(association)	0.530
	MYL12B	psi-mi:“MI:0914”(association)	0.460
ADD1	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
	DENR	psi-mi:“MI:0915”(physical association)	0.400
CSNK2B	ADD1	psi-mi:“MI:0915”(physical association)	0.370
GEMIN7	ADD1	psi-mi:“MI:0915”(physical association)	0.370
ADD1	MAP1LC3B	psi-mi:“MI:0915”(physical association)	0.370
TK1	ADD1	psi-mi:“MI:0915”(physical association)	0.370
ADD1	TPM3	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
TUBA1A	CAPZB	psi-mi:“MI:0914”(association)	0.350
TUBA1A	KIF2A	psi-mi:“MI:0914”(association)	0.350
PDHA1		psi-mi:“MI:0914”(association)	0.350

BioGRID (232): HMG20A (Two-hybrid), ADD1 (Two-hybrid), ADD1 (Affinity Capture-MS), ADD1 (Affinity Capture-MS), ADD1 (Affinity Capture-MS), ADD1 (Co-fractionation), ADD1 (Affinity Capture-MS), ACTA1 (Reconstituted Complex), ADD1 (Affinity Capture-MS), ADD1 (Proximity Label-MS), ADD1 (Affinity Capture-MS), ADD1 (Affinity Capture-MS), ADD1 (Affinity Capture-MS), ADD1 (Affinity Capture-MS), ADD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1U8QXK4, A2Q127, O04487, O14617, O75061, P06625, P08240, P12261, P15368, P26641, P26642, P29547, P29694, P30111, P35611, P36008, P40921, P54412, P78615, Q0II26, Q13155, Q17N71, Q27974, Q29387, Q32PX2, Q3MHE8, Q3SZV3, Q4R7H5, Q4WB03, Q5RA10, Q5Z627, Q68FR6, Q6PE25, Q6YW46, Q7PZD5, Q80TZ3, Q865S1, Q8R010, Q90YC0, Q91375

Diamond homologs: P35611, P35612, Q02645, Q05764, Q20952, Q5R5V7, Q5RA10, Q62847, Q63028, Q7LKY2, Q8GHB1, Q9A8Z4, Q9HYH5, Q9L9F0, Q9QYB5, Q9QYB8, Q9QYC0, Q9U9K0, Q9UEY8, Q9ZD54, A1AJA3, A7ZV69, A8A7U4, A9H8G1, A9N514, B1IT08, B1LQL8, B1XDU9, B1XPT3, B2TY70, B5BKK6, B5F3B4, B5Z2K4, B6I2A3, B7LCQ8, B7LLY0, B7M9G0, B7MLK3, B7MMH7, B7MSS8

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
ADD1	“form complex”	“4.1 complex”	binding
CDK5	“up-regulates activity”	ADD1	phosphorylation
PRKCA	up-regulates	ADD1	phosphorylation
PRKCZ	up-regulates	ADD1	phosphorylation
ROCK1	up-regulates	ADD1	phosphorylation
PRKACA	“down-regulates activity”	ADD1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 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
Regulation of actin dynamics for phagocytic cup formation	5	12.8×	3e-03
EPH-Ephrin signaling	5	11.5×	4e-03
L1CAM interactions	6	10.0×	3e-03
VEGFA-VEGFR2 Pathway	5	9.7×	6e-03
RHO GTPase Effectors	7	6.6×	4e-03
RHO GTPase cycle	7	5.8×	6e-03
Axon guidance	9	5.6×	3e-03
Nervous system development	9	5.4×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	5
Uncertain significance	93
Likely benign	8
Benign	7

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
145991	GRCh38/hg38 4p16.3(chr4:78578-3363219)x1	Pathogenic
146279	GRCh38/hg38 4p16.3-16.2(chr4:72555-4888108)x1	Pathogenic
147562	GRCh38/hg38 4p16.3(chr4:72555-3561655)x1	Pathogenic
147686	GRCh38/hg38 4p16.3(chr4:72555-4358718)x1	Pathogenic
147791	GRCh38/hg38 4p16.3(chr4:72555-3724047)x1	Pathogenic
150122	GRCh38/hg38 4p16.3(chr4:36424-3265531)x1	Pathogenic
150606	GRCh38/hg38 4p16.3(chr4:36424-4097002)x3	Pathogenic
150615	GRCh38/hg38 4p16.3(chr4:36424-3974044)x1	Pathogenic
153619	GRCh38/hg38 4p16.3-16.2(chr4:1964539-5912172)x1	Pathogenic
154884	GRCh38/hg38 4p16.3-16.1(chr4:36424-7359817)x1	Pathogenic
155180	GRCh38/hg38 4p16.3(chr4:36424-3881330)x1	Pathogenic
155480	GRCh38/hg38 4p16.3-16.1(chr4:68453-6055026)x1	Pathogenic
1707423	GRCh37/hg19 4p16.3-16.2(chr4:68345-5579467)x1	Pathogenic
219020	GRCh37/hg19 4p16.3-15.31(chr4:44020-19796182)x1	Pathogenic
252966	GRCh37/hg19 4p16.3-16.1(chr4:49450-8872474)x1	Pathogenic
2685952	GRCh37/hg19 4p16.3-16.1(chr4:68346-7171784)x3	Pathogenic
3062770	GRCh37/hg19 4p16.3(chr4:68345-3510024)x1	Pathogenic
3062771	GRCh37/hg19 4p16.3-16.1(chr4:68345-7923907)x1	Pathogenic
3062809	GRCh37/hg19 4p16.3(chr4:68346-3122209)x1	Pathogenic
3246727	NC_000004.11:g.(?1795662)(3495228_?)del	Pathogenic
3391882	GRCh37/hg19 4p16.3(chr4:68346-2948917)x1	Pathogenic
394609	GRCh37/hg19 4p16.3-q35.2(chr4:12440-190904441)x3	Pathogenic
4075872	GRCh37/hg19 4p16.3(chr4:68346-4376744)x1	Pathogenic
4075882	GRCh37/hg19 4p16.3(chr4:68346-3267849)x1	Pathogenic
4279476	GRCh37/hg19 4p16.3-16.2(chr4:68346-5762161)x1	Pathogenic
441927	GRCh37/hg19 4p16.3-16.2(chr4:68345-5319773)x1	Pathogenic
442177	GRCh37/hg19 4p16.3(chr4:68345-3891984)x1	Pathogenic
443042	GRCh37/hg19 4p16.3(chr4:68345-4044985)x1	Pathogenic
4682606	GRCh37/hg19 4p16.3-16.1(chr4:1752407-7489009)x1	Pathogenic
562881	GRCh37/hg19 4p16.3-16.2(chr4:2364201-5447465)x1	Pathogenic

SpliceAI

3828 predictions. Top by Δscore:

Variant	Effect	Δscore
4:2844023:AGGTG:A	donor_loss	1.0000
4:2844024:GGTG:G	donor_loss	1.0000
4:2876080:G:GT	donor_gain	1.0000
4:2876106:GCCCT:G	donor_gain	1.0000
4:2876111:G:GG	donor_gain	1.0000
4:2876120:G:GT	donor_gain	1.0000
4:2876139:G:GT	donor_gain	1.0000
4:2881894:TTA:T	acceptor_loss	1.0000
4:2881895:TAG:T	acceptor_loss	1.0000
4:2881897:G:GT	acceptor_loss	1.0000
4:2882037:G:GT	donor_gain	1.0000
4:2882056:CATGA:C	donor_gain	1.0000
4:2882057:ATGA:A	donor_gain	1.0000
4:2882058:TGA:T	donor_gain	1.0000
4:2882059:GA:G	donor_gain	1.0000
4:2882059:GAG:G	donor_gain	1.0000
4:2882061:G:GG	donor_gain	1.0000
4:2882061:GTG:G	donor_loss	1.0000
4:2884509:TTTCA:T	acceptor_loss	1.0000
4:2884510:TTCA:T	acceptor_loss	1.0000
4:2884511:TCA:T	acceptor_loss	1.0000
4:2884512:CAGGT:C	acceptor_loss	1.0000
4:2884513:A:AC	acceptor_loss	1.0000
4:2884514:GGT:G	acceptor_gain	1.0000
4:2884638:G:GA	donor_gain	1.0000
4:2884663:CACA:C	donor_gain	1.0000
4:2884664:ACA:A	donor_gain	1.0000
4:2884664:ACAG:A	donor_loss	1.0000
4:2884665:CA:C	donor_gain	1.0000
4:2884665:CAGTG:C	donor_loss	1.0000

AlphaMissense

5244 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:2881901:T:C	F67L	1.000
4:2881903:C:A	F67L	1.000
4:2881903:C:G	F67L	1.000
4:2881914:T:C	L71S	1.000
4:2876049:T:A	L45H	0.999
4:2876049:T:C	L45P	0.999
4:2876052:G:C	R46P	0.999
4:2876057:G:C	D48H	0.999
4:2876058:A:C	D48A	0.999
4:2876058:A:G	D48G	0.999
4:2876058:A:T	D48V	0.999
4:2876086:G:C	R57S	0.999
4:2876086:G:T	R57S	0.999
4:2876088:T:A	V58E	0.999
4:2876100:T:C	L62P	0.999
4:2876105:A:C	S64R	0.999
4:2876107:C:A	S64R	0.999
4:2876107:C:G	S64R	0.999
4:2881902:T:C	F67S	0.999
4:2881902:T:G	F67C	0.999
4:2881974:T:C	L91S	0.999
4:2881983:T:A	I94N	0.999
4:2881983:T:G	I94S	0.999
4:2881985:G:C	A95P	0.999
4:2898185:T:A	V248D	0.999
4:2899419:G:C	R382P	0.999
4:2899425:T:C	L384P	0.999
4:2899427:G:C	D385H	0.999
4:2899428:A:T	D385V	0.999
4:2907794:T:C	F489L	0.999

dbSNP variants (sampled 300 via entrez): RS1000002666 (4:2899930 G>T), RS1000009237 (4:2860569 G>A), RS1000035324 (4:2900219 G>A), RS1000035585 (4:2857270 T>C), RS1000103825 (4:2906078 T>G), RS1000107885 (4:2896128 C>G,T), RS1000111764 (4:2888509 G>A,C), RS1000122165 (4:2848433 A>G), RS1000142963 (4:2888216 G>A), RS1000168838 (4:2900482 C>T), RS1000185678 (4:2903814 T>C), RS1000186133 (4:2927730 A>T), RS1000217851 (4:2854849 C>T), RS1000236844 (4:2926928 A>G), RS1000268844 (4:2854440 T>A)

Disease associations

OMIM: gene MIM:102680 | disease phenotypes: MIM:118400, MIM:189960

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Semidominant

Mondo (3): cherubism (MONDO:0007315), neurodevelopmental disorder (MONDO:0700092), esophageal atresia/tracheoesophageal fistula (MONDO:0008586)

Orphanet (2): Cherubism (Orphanet:184), Esophageal atresia (Orphanet:1199)

HPO phenotypes

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

HPO	Term
HP:0001426	Non-Mendelian inheritance
HP:0004421	Elevated systolic blood pressure
HP:0004972	Elevated mean arterial pressure
HP:0005117	Elevated diastolic blood pressure

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004691_6	Huntington’s disease progression	3.000000e-06
GCST009523_22	Household income	1.000000e-08
GCST009524_46	Household income (MTAG)	9.000000e-10
GCST010108_3	Coffee consumption (cups per day)	3.000000e-10
GCST90002394_269	Monocyte percentage of white cells	1.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008336	disease progression measurement
EFO:0009695	household income
EFO:0006782	cups of coffee per day measurement
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002636	Cherubism	C05.116.099.708.375.199; C05.500.174; C07.320.173; C16.131.621.207.540.170; C16.320.170
D065886	Neurodevelopmental Disorders	F03.625
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4961	Efficacy	2B	hydrochlorothiazide	Essential hypertension;Hypertension
rs4961	Efficacy	3	diuretics	Hypertension;Myocardial Infarction
rs4961	Efficacy	3	bumetanide;furosemide;torasemide
rs4961	Efficacy	3	furosemide;spironolactone	Liver Cirrhosis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4961	ADD1	2B	11.50	4	bumetanide;furosemide;torasemide;diuretics;furosemide;spironolactone;hydrochlorothiazide

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	2
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Lead	affects splicing, decreases expression	2
Ozone	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
beta-lapachone	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
aflatoxin B2	increases methylation	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
rostafuroxin	affects cotreatment, affects response to substance	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Lycopene	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases oxidation	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Asbestos	affects expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	affects phosphorylation	1
Dimethyl Sulfoxide	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Gasoline	affects cotreatment, increases abundance, increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D2HX	Abcam Raji ADD1 KO	Cancer cell line	Male
CVCL_D9X7	Ubigene HeLa ADD1 KO	Cancer cell line	Female
CVCL_UQ08	Abcam Jurkat ADD1 KO	Cancer cell line	Male
CVCL_WQ92	Abcam K-562 ADD1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT03792360	PHASE1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge