DEAF1

Summary

DEAF1 (DEAF1 transcription factor, HGNC:14677) is a protein-coding gene on chromosome 11p15.5, encoding Deformed epidermal autoregulatory factor 1 homolog (O75398). Transcription factor that binds to sequence with multiple copies of 5’-TTC[CG]G-3’ present in its own promoter and that of the HNRPA2B1 gene.

This gene encodes a zinc finger domain-containing protein that functions as a regulator of transcription. The encoded proteins binds to its own promoter as well as to that of several target genes. Activity of this protein is important in the regulation of embryonic development. Mutations in this gene have been found in individuals with autosomal dominant cognitive disability. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10522 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, autosomal dominant 24 (Definitive, GenCC) — +3 more curated relationships
• Clinical variants (ClinVar): 1,087 total — 51 pathogenic, 45 likely-pathogenic
• Phenotypes (HPO): 58
• Transcription factor: yes — 14 downstream targets (CollecTRI)
• MANE Select transcript: NM_021008

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14677
Approved symbol	DEAF1
Name	DEAF1 transcription factor
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	NUDR, SPN, ZMYND5
Ensembl gene	ENSG00000177030
Ensembl biotype	protein_coding
OMIM	602635
Entrez	10522

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 11 protein_coding, 6 protein_coding_CDS_not_defined, 5 retained_intron, 5 nonsense_mediated_decay

ENST00000382409, ENST00000524786, ENST00000525626, ENST00000525904, ENST00000526790, ENST00000526857, ENST00000527170, ENST00000527658, ENST00000528864, ENST00000529717, ENST00000529727, ENST00000530813, ENST00000682936, ENST00000683307, ENST00000684249, ENST00000685854, ENST00000686001, ENST00000687329, ENST00000689835, ENST00000690068, ENST00000692634, ENST00000693164, ENST00000882097, ENST00000917805, ENST00000917806, ENST00000942421, ENST00000942422

RefSeq mRNA: 3 — MANE Select: NM_021008 NM_001293634, NM_001367390, NM_021008

CCDS: CCDS31327, CCDS91398

Canonical transcript exons

ENST00000382409 — 12 exons

Exon	Start	End
ENSE00001378328	686858	686997
ENSE00002181507	694759	695222
ENSE00003460414	678694	678822
ENSE00003469841	644233	644654
ENSE00003474998	688331	688460
ENSE00003553041	684898	684963
ENSE00003566516	691501	691598
ENSE00003580670	653962	654051
ENSE00003585529	687911	688057
ENSE00003594306	679688	679816
ENSE00003596812	680963	681089
ENSE00003630531	674536	674783

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.3821 / max 214.5284, expressed in 1815 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117808	18.4752	1799
117809	1.0472	702
117812	0.6749	407
117810	0.5934	304
117813	0.5913	381

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
amygdala	UBERON:0001876	98.39	gold quality
temporal lobe	UBERON:0001871	98.38	gold quality
Ammon’s horn	UBERON:0001954	98.17	gold quality
anterior cingulate cortex	UBERON:0009835	98.03	gold quality
right frontal lobe	UBERON:0002810	97.81	gold quality
frontal cortex	UBERON:0001870	97.61	gold quality
prefrontal cortex	UBERON:0000451	97.58	gold quality
cerebral cortex	UBERON:0000956	97.54	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.38	gold quality
nucleus accumbens	UBERON:0001882	97.25	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.23	gold quality
cerebellum	UBERON:0002037	97.21	gold quality
putamen	UBERON:0001874	97.20	gold quality
cerebellar cortex	UBERON:0002129	97.19	gold quality
cerebellar hemisphere	UBERON:0002245	97.19	gold quality
hypothalamus	UBERON:0001898	97.04	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.99	gold quality
caudate nucleus	UBERON:0001873	96.94	gold quality
primary visual cortex	UBERON:0002436	96.79	gold quality
superior frontal gyrus	UBERON:0002661	96.78	gold quality
brain	UBERON:0000955	96.70	gold quality
substantia nigra	UBERON:0002038	96.17	gold quality
lower esophagus mucosa	UBERON:0035834	96.16	gold quality
left lobe of thyroid gland	UBERON:0001120	95.43	gold quality
right lobe of thyroid gland	UBERON:0001119	95.21	gold quality
cortical plate	UBERON:0005343	95.20	gold quality
thyroid gland	UBERON:0002046	95.10	gold quality
metanephros cortex	UBERON:0010533	94.96	gold quality
cortex of kidney	UBERON:0001225	93.78	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.15

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

14 targets.

Target	Regulation
CASP3
DEAF1	Repression
EIF4G3
EN1	Activation
F11
F2
GDF5	Unknown
HNRNPA2B1	Repression
HTR1A	Repression
PDYN	Activation
PENK	Activation
POU6F1
RAC3	Activation
SRPX

Upstream regulators (CollecTRI, top): DEAF1

miRNA regulators (miRDB)

13 targeting DEAF1, 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-6721-5P	99.93	68.92	2981
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-4790-5P	96.67	67.45	167
HSA-MIR-7109-3P	94.23	67.19	743

Literature-anchored findings (GeneRIF, showing 25)

• The spn gene was mutated in the primary CRC, the expression of SPN was primarily cytoplasmic in nonmucinous CRCs and nuclear in mucinous CRCs. (PMID:11705868)
• DEAF1 has nuclear export signal and protein interaction domains (PMID:15161925)
• Cell-specific regulation by Deaf-1 could underlie region-specific alterations in 5-HT1A receptor expression in different mood disorders. (PMID:16467535)
• In this study the NUDR immunoreactivity as measured by Western blot was significantly decreased in the prefrontal cortex of female depressed subjects (42%, p=0.02) and unchanged in male depressed subjects relative to gender-matched control subjects. (PMID:18561871)
• Overexpression of transgenic DEAF-1 in human breast epithelial cells enhances cell proliferation. (PMID:18826651)
• DEAF-1 is a trans-acting factor that merits further investigation as a potential tool for modulating GDF5 expression. (PMID:19565498)
• Lower peripheral tissue antigens (PTA) expression resulting from the alternative splicing of DEAF1 may contribute to the pathogenesis of type 1 diabetes. (PMID:19668219)
• These results suggest that transcription factors such as Aire and Deaf1, which exert global transcriptional regulatory functions, may play important roles in self-renewal of ESCs and maintaining ESC in a transcriptionally hyperactive state. (PMID:20226168)
• Data identify DEAF1 as an interactor and in vitro substrate of GSK3A and GSK3B that interacts with the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway. (PMID:20368287)
• Non-genomic downregulation of 5-HT1A receptor by 17beta-estradiol does not involve NUDR and Freud-1 proteins. (PMID:22328058)
• DEAF1 can interact with the DNA-PK complex through interactions of its DNA binding domain with the carboxy-terminal region of Ku70 that contains the Bax binding domain, and that DEAF1 is a potential substrate for DNA-PK. (PMID:22442688)
• Pellino1 interacts with the transcription factor Deformed Epidermal Autoregulatory Factor 1 (DEAF1). (PMID:23846693)
• This study indicates, for the first time, a hereditary role of DEAF1 in white matter abnormalities, microcephaly and syndromic intellectual disability. (PMID:24668509)
• these results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1. (PMID:24726472)
• These data suggest that during the progression of type 1 diabetes, inflammation and hyperglycemia mediate the splicing of DEAF1 and loss of peripheral tissue antigen expression. (PMID:25187368)
• an autosomal recessive splice acceptor mutation in DEAF1 (c.997+4A>C, p.G292Pfs*) in all affected individuals, which led to exon skipping, and reduced the normal full-length mRNA copy number in the patients with epilepsy and extrapyramidal symptoms (PMID:26048982)
• Data show that deformed epidermal autoregulatory factor-1 (DEAF1) was located in the nucleus under the fluorescence microscope. (PMID:26271982)
• RAI1 polymorphisms rs4925102 and rs9907986 are predicted to disrupt the binding of retinoic acid RXR-RAR receptors and the transcription factor DEAF1, respectively, in Smith-Magenis and Potocki-Lupski syndromes patients. (PMID:26743651)
• We conclude that this DEAF1 gene alteration caused this patient’s symptoms and that white matter disease should not be considered a obligate feature of this syndrome. (PMID:26834045)
• identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1 (PMID:28213671)
• The results demonstrate that variants located within the neurodevelopmental disorder (DAND)or NLS domains significantly reduce DEAF1 transcriptional regulatory activities and are thus, likely to contribute to the underlying clinical concerns in DAND patients. (PMID:28940898)
• We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. (PMID:30923367)
• this study shows that Deaf1 promotes eccrine gland formation (PMID:31145909)
• De novo variants of DEAF1 cause intellectual disability in six Chinese patients. (PMID:33705764)
• Transcriptional Regulation of the Human 5-HT1A Receptor Gene by Lithium: Role of Deaf1 and GSK3beta. (PMID:37958600)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	deaf1	ENSDARG00000088844
mus_musculus	Deaf1	ENSMUSG00000058886
rattus_norvegicus	Deaf1	ENSRNOG00000017960
drosophila_melanogaster	Deaf1	FBGN0013799

Protein

Protein identifiers

Deformed epidermal autoregulatory factor 1 homolog — O75398 (reviewed: O75398)

Alternative names: Nuclear DEAF-1-related transcriptional regulator, Suppressin, Zinc finger MYND domain-containing protein 5

All UniProt accessions (11): O75398, A0A804HIS1, A0A8I5KQJ8, A0A8I5KQY1, A0A8I5KR93, A0A8I5KUA2, A0A8I5KZ80, A0A8I5QJC6, A0A8I5QL28, H0YCH1, H0YCY2

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds to sequence with multiple copies of 5’-TTC[CG]G-3’ present in its own promoter and that of the HNRPA2B1 gene. Down-regulates transcription of these genes. Binds to the retinoic acid response element (RARE) 5’-AGGGTTCACCGAAAGTTCA-3’. Activates the proenkephalin gene independently of promoter binding, probably through protein-protein interaction. When secreted, behaves as an inhibitor of cell proliferation, by arresting cells in the G0 or G1 phase. Required for neural tube closure and skeletal patterning. Regulates epithelial cell proliferation and side-branching in the mammary gland. Controls the expression of peripheral tissue antigens in pancreatic lymph nodes. Isoform 1 displays greater transcriptional activity than isoform 4. Isoform 4 may inhibit transcriptional activity of isoform 1 by interacting with isoform 1 and retaining it in the cytoplasm. Transcriptional activator of EIF4G3.

Subunit / interactions. Homodimer. Isoform 1 and isoform 4 may form a heterodimer. Interacts with LMO2 and CLIM2. Interacts with LMO4; LMO4 blocks export from nucleus. May interact with the corepressors NCOR1 and NCRO2. Identified in a complex with the XRCC5 and XRCC6 heterodimer. Interacts (via the SAND domain) with the DNA-PK complex subunit XRCC6; the interaction is direct and may be inhibited by DNA-binding.

Subcellular location. Nucleus. Cytoplasm Secreted Secreted Cytoplasm.

Tissue specificity. Expressed in various tissues and cells such as in peripheral mononuclear cells and hormone-secreting pituitary cells. Expression in pancreatic lymph nodes of patients with type 1 diabetes is 20 times higher than in healthy controls. Highly expressed in fetal and adult brain.

Post-translational modifications. May be phosphorylated by DNA-PK complex in a DNA independent manner (in vitro).

Disease relevance. Vulto-van Silfout-de Vries syndrome (VSVS) [MIM:615828] An autosomal dominant disorder characterized by intellectual disability, poor speech, motor delay, and autistic features. Most patients have additional non-specific features, including hypotonia and gait abnormalities, seizures, which may be refractory, high pain threshold, and sleep disturbances. The disease is caused by variants affecting the gene represented in this entry. Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures (NEDHELS) [MIM:617171] An autosomal recessive disorder characterized by psychomotor delay, epilepsy, intellectual disability, speech impairment and dyskinesia of the limbs. Patients also manifest autistic features and other behavioral abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Defective DEAF1 could confer a growth advantage to the mutated cells influencing the development and progression of neoplasia, e.g. in the case of colorectal carcinomas. Subcellular location in colorectal carcinomas (cytoplasmic or nuclear) is a prognostic factor that identifies a subgroup of patients with reduced survival. In addition, changes in the subcellular location correlates with the proliferative status of the cells. Has no predictable signal peptide.

Isoforms (4)

UniProt ID	Names	Canonical?
O75398-1	1, Hu-DF1	yes
O75398-3	2, NUDR8
O75398-4	3, Suppressin
O75398-5	4, Hu-DF1-VAR

RefSeq proteins (3): NP_001280563, NP_001354319, NP_066288* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000770	SAND_dom	Domain
IPR002893	Znf_MYND	Domain
IPR010919	SAND-like_dom_sf	Homologous_superfamily
IPR024119	TF_DEAF-1	Family

Pfam: PF01342, PF01753

UniProt features (79 total): sequence variant 29, mutagenesis site 9, binding site 8, sequence conflict 7, modified residue 5, splice variant 4, region of interest 3, helix 3, strand 3, turn 3, chain 1, domain 1, zinc finger region 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5UWW	X-RAY DIFFRACTION	2.15
2JW6	SOLUTION NMR
4A24	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75398-F1	61.62	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.

Ligand- & substrate-binding residues (8): 515; 518; 524; 528; 536; 540; 504; 507

Post-translational modifications (5): 171, 176, 179, 432, 448

Mutagenesis-validated functional residues (9):

Position	Phenotype
215	reduces transcription activation.
226	reduces transcription activation.
246	reduces transcription activation.
250	abolishes dna-binding. loss of deaf1-promoter repression; when associated with a-253. loss of transcriptional activation
252	abolishes dna-binding.
253	abolishes dna-binding. oss of deaf1-promoter repression; when associated with a-250. loss of transcriptional activation
302	abolishes nuclear localization.
304	abolishes nuclear localization.
538	no effect on folding of mynd-type zinc finger.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 598 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_COGNITION, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_BEHAVIOR, GOBP_REGULATION_OF_MAMMARY_GLAND_EPITHELIAL_CELL_PROLIFERATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (13): negative regulation of transcription by RNA polymerase II (GO:0000122), behavioral fear response (GO:0001662), neural tube closure (GO:0001843), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), germ cell development (GO:0007281), visual learning (GO:0008542), anatomical structure morphogenesis (GO:0009653), regulation of mammary gland epithelial cell proliferation (GO:0033599), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), embryonic skeletal system development (GO:0048706), nervous system development (GO:0007399)

GO Molecular Function (7): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), zinc ion binding (GO:0008270), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): chromatin (GO:0000785), fibrillar center (GO:0001650), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), RNA polymerase II transcription regulator complex (GO:0090575)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
regulation of DNA-templated transcription	3
DNA-templated transcription	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
negative regulation of DNA-templated transcription	1
behavioral defense response	1
fear response	1
primary neural tube formation	1
tube closure	1
developmental process involved in reproduction	1
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
visual behavior	1
associative learning	1
developmental process	1
anatomical structure development	1
mammary gland epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
skeletal system development	1
chordate embryonic development	1
system development	1
transcription cis-regulatory region binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transition metal ion binding	1
nucleic acid binding	1
binding	1
cation binding	1
chromosome	1
nucleolus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

666 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DEAF1	ZMYND11	Q15326	885
DEAF1	ZMYND19	Q96E35	810
DEAF1	AIRE	O43918	670
DEAF1	MCHR1	Q99705	650
DEAF1	CC2D1A	Q6P1N0	622
DEAF1	FAM170A	A1A519	587
DEAF1	LDB1	Q86U70	570
DEAF1	SMYD1	Q8NB12	558
DEAF1	SMYD2	Q9NRG4	550
DEAF1	SMYD3	Q9H7B4	535
DEAF1	SMYD5	Q6GMV2	523
DEAF1	RBBP8	Q99708	510
DEAF1	BRCA1	P38398	509
DEAF1	HTR1A	P08908	494
DEAF1	BMPR1A	P36894	492

IntAct

53 interactions, top by confidence:

A	B	Type	Score
DEAF1	FHL2	psi-mi:“MI:0915”(physical association)	0.680
GSK3A	DEAF1	psi-mi:“MI:0915”(physical association)	0.650
DEAF1	MECP2	psi-mi:“MI:0915”(physical association)	0.590
DEAF1	XRCC6	psi-mi:“MI:0914”(association)	0.580
DEAF1	XRCC6	psi-mi:“MI:0915”(physical association)	0.580
XRCC6	DEAF1	psi-mi:“MI:0915”(physical association)	0.580
DEAF1	CEP76	psi-mi:“MI:0915”(physical association)	0.560
DEAF1	SNCA	psi-mi:“MI:0915”(physical association)	0.560
DEAF1	TARDBP	psi-mi:“MI:0915”(physical association)	0.560
DEAF1	GSK3B	psi-mi:“MI:0915”(physical association)	0.520
GSK3B	DEAF1	psi-mi:“MI:0915”(physical association)	0.520
DEAF1	CDKN2A	psi-mi:“MI:0915”(physical association)	0.510
DEAF1	PRKDC	psi-mi:“MI:0915”(physical association)	0.400
LTBR	DEAF1	psi-mi:“MI:0915”(physical association)	0.400
DEAF1	FXR1	psi-mi:“MI:0915”(physical association)	0.370
DEAF1	FXR2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (65): DEAF1 (Affinity Capture-MS), SP1 (Affinity Capture-Western), SUB1 (Affinity Capture-Western), SP3 (Affinity Capture-Western), DEAF1 (Affinity Capture-Western), DEAF1 (Affinity Capture-Western), DEAF1 (Two-hybrid), DEAF1 (Affinity Capture-MS), DEAF1 (Two-hybrid), DEAF1 (Two-hybrid), DEAF1 (Two-hybrid), DEAF1 (Negative Genetic), DEAF1 (Two-hybrid), DEAF1 (Affinity Capture-RNA), DEAF1 (Two-hybrid)

ESM2 similar proteins: A2VE44, A7YY54, O00268, O00287, O35274, O35779, O75398, O77562, O77638, O88450, O95644, P12755, P15066, P17535, P17544, P22670, P48377, P52909, P78424, Q07916, Q13469, Q14863, Q3UR85, Q5R9C9, Q60591, Q69Z61, Q6R891, Q6T4P5, Q86YP4, Q8BJI4, Q8CHY6, Q8CIE2, Q8NF64, Q8R0S1, Q8R3B7, Q8TEK3, Q8VCG9, Q8VHR5, Q8WXI9, Q96N64

Diamond homologs: O00268, O43439, O54972, O70374, O75081, O75398, O77562, O88450, P47825, Q06455, Q5F3B1, Q61909, Q9IAB2, Q9Z1T5, O88873, P23497, P58929, Q13342, Q3KRF1, Q8BVK9, Q921C6, Q9H930, Q9HB58, Q9UKD1, Q24180, Q18171, Q2HJ87, Q9JL60, Q9QUZ8, Q9Y692, A9RA84, B0CM99, B1MTB0, B2RPK0, O04235, O15347, O35892, O35893, O49596, O54879

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
DEAF1	“down-regulates quantity by repression”	HTR1A	“transcriptional regulation”
DEAF1	“up-regulates quantity by expression”	RAC3	“transcriptional regulation”
DEAF1	“up-regulates quantity by expression”	EN1	“transcriptional regulation”
MECP2	“up-regulates activity”	DEAF1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 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.

GO biological processes:

GO term	Partners	Fold	FDR
protein stabilization	5	10.1×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1087 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	51
Likely pathogenic	45
Uncertain significance	526
Likely benign	346
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1098350	NM_021008.4(DEAF1):c.634G>T (p.Gly212Cys)	Pathogenic
1184966	NM_021008.4(DEAF1):c.578_579insAAAA (p.Asn193fs)	Pathogenic
133291	NM_021008.4(DEAF1):c.683T>G (p.Ile228Ser)	Pathogenic
133294	NM_021008.4(DEAF1):c.762A>C (p.Arg254Ser)	Pathogenic
1342716	NM_021008.4(DEAF1):c.719T>C (p.Phe240Ser)	Pathogenic
1363866	NC_000011.9:g.(?691481)(691618_?)del	Pathogenic
1380773	NM_021008.4(DEAF1):c.484_496del (p.Gly162fs)	Pathogenic
1450184	NM_021008.4(DEAF1):c.1412del (p.Lys471fs)	Pathogenic
1450281	NM_021008.4(DEAF1):c.106G>T (p.Glu36Ter)	Pathogenic
1451880	NM_021008.4(DEAF1):c.823C>T (p.His275Tyr)	Pathogenic
1456124	NM_021008.4(DEAF1):c.815T>C (p.Leu272Ser)	Pathogenic
1460463	NM_021008.4(DEAF1):c.794dup (p.Cys265fs)	Pathogenic
1676838	NM_021008.4(DEAF1):c.815T>G (p.Leu272Ter)	Pathogenic
1685692	NM_021008.4(DEAF1):c.883A>G (p.Arg295Gly)	Pathogenic
1687234	NM_021008.4(DEAF1):c.674G>A (p.Gly225Glu)	Pathogenic
1974517	NM_021008.4(DEAF1):c.907C>T (p.Arg303Cys)	Pathogenic
2026917	NM_021008.4(DEAF1):c.1132G>T (p.Glu378Ter)	Pathogenic
2030840	NM_021008.4(DEAF1):c.642_643del (p.Tyr215fs)	Pathogenic
2041708	NM_021008.4(DEAF1):c.837C>G (p.Cys279Trp)	Pathogenic
2085378	NM_021008.4(DEAF1):c.1383C>A (p.Asn461Lys)	Pathogenic
2202296	NM_021008.4(DEAF1):c.118_131dup (p.Arg44delinsSerArgCysTer)	Pathogenic
2421207	NM_021008.4(DEAF1):c.751G>A (p.Asp251Asn)	Pathogenic
2426646	NC_000011.9:g.(?694739)(695047_?)del	Pathogenic
2426647	NC_000011.9:g.(?674516)(674803_?)del	Pathogenic
2426649	NC_000011.9:g.(?678674)(681109_?)del	Pathogenic
2571614	NM_021008.4(DEAF1):c.674G>T (p.Gly225Val)	Pathogenic
2757965	NM_021008.4(DEAF1):c.662C>T (p.Ser221Leu)	Pathogenic
2761468	NM_021008.4(DEAF1):c.781del (p.Arg261fs)	Pathogenic
2822067	NM_021008.4(DEAF1):c.870+5G>A	Pathogenic
2843031	NM_021008.4(DEAF1):c.499del (p.Ala167fs)	Pathogenic

SpliceAI

3678 predictions. Top by Δscore:

Variant	Effect	Δscore
11:644652:GTCC:G	acceptor_loss	1.0000
11:644655:C:CC	acceptor_gain	1.0000
11:653959:TA:T	donor_loss	1.0000
11:653961:C:CA	donor_loss	1.0000
11:653961:CCTTG:C	donor_gain	1.0000
11:654047:GACTG:G	acceptor_gain	1.0000
11:654049:CTG:C	acceptor_gain	1.0000
11:654050:TG:T	acceptor_gain	1.0000
11:654050:TGCTG:T	acceptor_loss	1.0000
11:654051:GCTGC:G	acceptor_loss	1.0000
11:654052:C:CC	acceptor_gain	1.0000
11:654053:T:C	acceptor_loss	1.0000
11:674516:C:A	donor_gain	1.0000
11:674790:CATT:C	acceptor_gain	1.0000
11:674793:T:C	acceptor_gain	1.0000
11:674793:T:TC	acceptor_gain	1.0000
11:678823:C:CC	acceptor_gain	1.0000
11:679817:C:CC	acceptor_gain	1.0000
11:684896:A:AC	donor_gain	1.0000
11:684897:C:CC	donor_gain	1.0000
11:684971:G:C	acceptor_gain	1.0000
11:686853:GATAC:G	donor_loss	1.0000
11:686854:ATACC:A	donor_loss	1.0000
11:686855:TACC:T	donor_loss	1.0000
11:686856:ACCT:A	donor_loss	1.0000
11:686857:C:CT	donor_loss	1.0000
11:686915:A:AC	donor_gain	1.0000
11:686916:C:CC	donor_gain	1.0000
11:686916:CTG:C	donor_gain	1.0000
11:686993:GCCGC:G	acceptor_gain	1.0000

AlphaMissense

3644 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:644649:C:A	W533C	1.000
11:644649:C:G	W533C	1.000
11:653971:G:C	C528W	1.000
11:653972:C:G	C528S	1.000
11:653972:C:T	C528Y	1.000
11:653973:A:G	C528R	1.000
11:653973:A:T	C528S	1.000
11:653983:G:C	C524W	1.000
11:653984:C:G	C524S	1.000
11:653984:C:T	C524Y	1.000
11:653985:A:G	C524R	1.000
11:653985:A:T	C524S	1.000
11:654003:A:G	C518R	1.000
11:654010:G:C	C515W	1.000
11:654011:C:G	C515S	1.000
11:654012:A:G	C515R	1.000
11:654012:A:T	C515S	1.000
11:654034:G:C	C507W	1.000
11:654035:C:G	C507S	1.000
11:654035:C:T	C507Y	1.000
11:654036:A:G	C507R	1.000
11:654036:A:T	C507S	1.000
11:654043:G:C	C504W	1.000
11:654044:C:G	C504S	1.000
11:654044:C:T	C504Y	1.000
11:654045:A:G	C504R	1.000
11:654045:A:T	C504S	1.000
11:674630:A:G	L470P	1.000
11:681054:C:A	R302S	1.000
11:681054:C:G	R302S	1.000

dbSNP variants (sampled 300 via entrez): RS1000014205 (11:674075 C>T), RS1000028810 (11:650040 C>A,T), RS1000101704 (11:703659 C>A,T), RS1000123011 (11:681297 C>T), RS1000145476 (11:652679 T>A,C), RS1000154627 (11:668349 A>G), RS1000169335 (11:645801 C>T), RS1000207592 (11:681536 G>A), RS1000234161 (11:654738 G>A), RS1000245467 (11:654953 G>A), RS1000275631 (11:689380 C>A,T), RS1000327480 (11:684250 T>C), RS1000395029 (11:650146 G>A,C), RS1000402552 (11:684499 G>A,C), RS1000472372 (11:704914 G>A,T)

Disease associations

OMIM: gene MIM:602635 | disease phenotypes: MIM:615828, MIM:617171, MIM:209850, MIM:176700

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 24	Definitive	Autosomal dominant
intellectual disability-epilepsy-extrapyramidal syndrome	Strong	Autosomal recessive
complex neurodevelopmental disorder	Strong	Semidominant
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant

Mondo (12): intellectual disability, autosomal dominant 24 (MONDO:0014357), intellectual disability (MONDO:0001071), intellectual disability-epilepsy-extrapyramidal syndrome (MONDO:0014952), prostate cancer (MONDO:0008315), autism spectrum disorder (MONDO:0005258), autosomal dominant non-syndromic intellectual disability (MONDO:0015802), autism, susceptiblity to (MONDO:0020836), autism (MONDO:0005260), attention deficit-hyperactivity disorder (MONDO:0007743), autosomal dominant prognathism (MONDO:0008312), obesity disorder (MONDO:0011122), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (8): Intellectual disability-epilepsy-extrapyramidal syndrome (Orphanet:468620), Familial prostate cancer (Orphanet:1331), Autosomal dominant non-syndromic intellectual disability (Orphanet:178469), Autosomal dominant prognathism (Orphanet:2964), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000349	Widow’s peak
HP:0000582	Upslanted palpebral fissure
HP:0000712	Emotional lability
HP:0000713	Agitation
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000817	Reduced eye contact
HP:0000960	Sacral dimple
HP:0001212	Prominent fingertip pads
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001288	Gait disturbance
HP:0001344	Absent speech
HP:0001382	Joint hypermobility
HP:0002007	Frontal bossing
HP:0002019	Constipation

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008313	Malocclusion, Angle Class III	C07.793.494.650
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4963126	DEAF1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cocaine	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
methylselenic acid	decreases expression	1
beta-lapachone	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	decreases expression	1
nickel sulfate	increases expression	1
coumarin	increases phosphorylation	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
NSC 689534	affects binding, decreases expression	1
Bortezomib	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects expression, increases abundance	1
Caffeine	increases phosphorylation	1
Copper	affects binding, decreases expression	1
Cycloheximide	affects cotreatment, increases expression	1
Heroin	decreases expression	1
Doxorubicin	decreases expression	1
Methylnitronitrosoguanidine	decreases expression	1
Ozone	affects expression, increases abundance	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression, affects cotreatment	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1