IRF2BPL

Summary

IRF2BPL (interferon regulatory factor 2 binding protein like, HGNC:14282) is a protein-coding gene on chromosome 14q24.3, encoding Probable E3 ubiquitin-protein ligase IRF2BPL (Q9H1B7). Probable E3 ubiquitin protein ligase involved in the proteasome-mediated ubiquitin-dependent degradation of target proteins.

This gene encodes a transcription factor that may play a role in regulating female reproductive function.

Source: NCBI Gene 64207 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegenerative disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 569 total — 43 pathogenic, 44 likely-pathogenic
• Phenotypes (HPO): 29
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_024496

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14282
Approved symbol	IRF2BPL
Name	interferon regulatory factor 2 binding protein like
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	EAP1, KIAA1865
Ensembl gene	ENSG00000119669
Ensembl biotype	protein_coding
OMIM	611720
Entrez	64207

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000238647

RefSeq mRNA: 1 — MANE Select: NM_024496 NM_024496

CCDS: CCDS9854

Canonical transcript exons

ENST00000238647 — 1 exons

Exon	Start	End
ENSE00001401427	77024543	77028708

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.8586 / max 297.0474, expressed in 1802 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144198	23.7086	1793
144197	5.0310	1559
144196	0.6603	415
144192	0.3373	162
144191	0.1214	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	99.47	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.43	gold quality
endothelial cell	CL:0000115	99.39	gold quality
parotid gland	UBERON:0001831	99.27	gold quality
epithelial cell of pancreas	CL:0000083	99.25	gold quality
epithelium of mammary gland	UBERON:0003244	99.25	gold quality
mammary duct	UBERON:0001765	99.24	gold quality
oviduct epithelium	UBERON:0004804	99.22	gold quality
left ventricle myocardium	UBERON:0006566	99.11	gold quality
visceral pleura	UBERON:0002401	99.05	gold quality
upper arm skin	UBERON:0004263	99.03	gold quality
caput epididymis	UBERON:0004358	98.91	gold quality
palpebral conjunctiva	UBERON:0001812	98.88	gold quality
parietal pleura	UBERON:0002400	98.85	gold quality
cauda epididymis	UBERON:0004360	98.75	gold quality
corpus epididymis	UBERON:0004359	98.61	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.61	gold quality
kidney epithelium	UBERON:0004819	98.59	gold quality
renal medulla	UBERON:0000362	98.52	gold quality
gingival epithelium	UBERON:0001949	98.51	gold quality
pigmented layer of retina	UBERON:0001782	98.48	gold quality
lower lobe of lung	UBERON:0008949	98.46	gold quality
retina	UBERON:0000966	98.45	gold quality
nipple	UBERON:0002030	98.42	gold quality
gingiva	UBERON:0001828	98.23	gold quality
skin of hip	UBERON:0001554	98.15	gold quality
epithelium of nasopharynx	UBERON:0001951	98.15	gold quality
tibialis anterior	UBERON:0001385	98.03	gold quality
secondary oocyte	CL:0000655	98.02	gold quality
pericardium	UBERON:0002407	98.00	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	3044.86
E-MTAB-7008	yes	112.99
E-ANND-3	yes	11.66

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
GNRH1	Activation
IRF2BPL	Unknown
KISS1	Repression
PDYN	Repression
PENK	Repression

Upstream regulators (CollecTRI, top): CUX1, FOXF2, IRF2BPL, NKX2-1, YY1

miRNA regulators (miRDB)

102 targeting IRF2BPL, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-182-5P	99.87	74.03	2589

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 8)

• C14orf4 encodes a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function (PMID:17627301)
• These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies. (PMID:30166628)
• IRF2BPL gene variants: One new case. (PMID:31729144)
• [Clinical features of epilepsy in children with IRF2BPL gene variation]. (PMID:34102826)
• Adult onset familiar dystonia-plus syndrome: A novel presentation of IRF2BPL-associated neurodegeneration. (PMID:34864472)
• IRF2BPL as a novel causative gene for progressive myoclonus epilepsy. (PMID:37114479)
• De novo variants of IRF2BPL result in developmental epileptic disorder. (PMID:38481258)
• Genetic analysis of IRF2BPL in a Taiwanese dystonia cohort: The genotype and phenotype correlation. (PMID:38650104)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	irf2bpl	ENSDARG00000004297
mus_musculus	Irf2bpl	ENSMUSG00000034168
rattus_norvegicus	Irf2bpl	ENSRNOG00000011026
drosophila_melanogaster	Pits	FBGN0030400
caenorhabditis_elegans	ztf-11	WBGENE00009939
caenorhabditis_elegans		WBGENE00010867

Paralogs (5): ST18 (ENSG00000147488), IRF2BP2 (ENSG00000168264), IRF2BP1 (ENSG00000170604), MYT1L (ENSG00000186487), MYT1 (ENSG00000196132)

Protein

Protein identifiers

Probable E3 ubiquitin-protein ligase IRF2BPL — Q9H1B7 (reviewed: Q9H1B7)

Alternative names: Enhanced at puberty protein 1, Interferon regulatory factor 2-binding protein-like

All UniProt accessions (1): Q9H1B7

UniProt curated annotations — full annotation on UniProt →

Function. Probable E3 ubiquitin protein ligase involved in the proteasome-mediated ubiquitin-dependent degradation of target proteins. Through the degradation of CTNNB1, functions downstream of FOXF2 to negatively regulate the Wnt signaling pathway. Probably plays a role in the development of the central nervous system and in neuronal maintenance. Also acts as a transcriptional regulator of genes controlling female reproductive function. May play a role in gene transcription by transactivating GNRH1 promoter and repressing PENK promoter.

Subunit / interactions. Interacts with CTNNB1.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in the heart, moderately in skeletal muscle and pancreas, and weakly in brain, kidney, liver, testis, thyroid gland and lymphocytes.

Disease relevance. Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS) [MIM:618088] An autosomal dominant disorder characterized by global developmental delay or neurodevelopmental regression, hypotonia, progressive ataxia, intellectual disability, seizures, and abnormal movements. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Polymorphism. The poly-Gln region is polymorphic; the most frequent allele contained 24 Gln. Stretches of 20-31 Gln are observed in healthy individuals.

Similarity. Belongs to the IRF2BP family.

RefSeq proteins (1): NP_078772* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022750	IRF-2BP1_2-like_Znf	Domain
IPR044882	I2BP1/2_C3HC4-RING_sf	Homologous_superfamily
IPR057414	Zf-C3HC4_IRF-2BP1_2	Domain
IPR058682	IRF-2BP1/2-like_M	Domain

Pfam: PF11261, PF25454, PF25457

UniProt features (39 total): modified residue 9, compositionally biased region 8, sequence variant 7, strand 4, region of interest 3, helix 2, coiled-coil region 2, chain 1, zinc finger region 1, cross-link 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2CS3	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H1B7-F1	62.01	0.24

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 (10): 69, 215, 519, 547, 639, 657, 658, 659, 662, 79

Mutagenesis-validated functional residues (1):

Position	Phenotype
715	loss of transcription activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 260 (showing top): ATF_B, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GGTGTGT_MIR329, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, SP3_Q3, CREBP1_Q2, TGACCTY_ERR1_Q2, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, SHEPARD_BMYB_MORPHOLINO_DN, NFKB_Q6, CREB_Q4, GTGCCTT_MIR506, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, AGTCTTA_MIR499

GO Biological Process (5): negative regulation of transcription by RNA polymerase II (GO:0000122), nervous system development (GO:0007399), protein ubiquitination (GO:0016567), positive regulation of transcription by RNA polymerase II (GO:0045944), development of animal secondary female sexual characteristics (GO:0046543)

GO Molecular Function (5): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	1
system development	1
protein modification by small protein conjugation	1
positive regulation of DNA-templated transcription	1
development of animal secondary sexual characteristics	1
female sex differentiation	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

789 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRF2BPL	GNRH1	P01148	801
IRF2BPL	IRF2	P14316	630
IRF2BPL	KISS1	Q15726	447
IRF2BPL	IRF2BP2	Q7Z5L9	432
IRF2BPL	IRF2BP1	Q8IU81	426
IRF2BPL	KISS1R	Q969F8	393
IRF2BPL	FOXF2	Q12947	371
IRF2BPL	TAC3	Q9UHF0	348
IRF2BPL	ITGB3BP	Q13352	341
IRF2BPL	KBTBD3	Q8NAB2	339
IRF2BPL	NKX2-1	P43699	324
IRF2BPL	FASTKD2	Q9NYY8	321
IRF2BPL	RBM19	Q9Y4C8	307
IRF2BPL	NACC1	Q96RE7	306
IRF2BPL	RANBP17	Q9H2T7	306

IntAct

40 interactions, top by confidence:

A	B	Type	Score
DCK	DGUOK	psi-mi:“MI:0914”(association)	0.620
FOSL2	ZZEF1	psi-mi:“MI:0914”(association)	0.530
IRF2	CTSS	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
IRF2BP1	SCRIB	psi-mi:“MI:0914”(association)	0.530
IRF2BP1	VGLL4	psi-mi:“MI:0914”(association)	0.530
VGLL4	IRF2BP2	psi-mi:“MI:0914”(association)	0.530
VGLL4	YAP1	psi-mi:“MI:0914”(association)	0.530
VGLL4	TEAD1	psi-mi:“MI:0914”(association)	0.480
TSG101	IRF2BPL	psi-mi:“MI:0407”(direct interaction)	0.440
IRF2BPL	UBE2Q1	psi-mi:“MI:0915”(physical association)	0.370
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
IRF2	VWA8	psi-mi:“MI:0914”(association)	0.350
VGLL4	TEAD1	psi-mi:“MI:0914”(association)	0.350
IRF2BP1	IRF2BP2	psi-mi:“MI:0914”(association)	0.350
SCRIB	C1orf226	psi-mi:“MI:0914”(association)	0.350
KCTD17	PXDNL	psi-mi:“MI:0914”(association)	0.350
BAG2	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
DCK	KLK3	psi-mi:“MI:0914”(association)	0.350
IRF2	AP5Z1	psi-mi:“MI:0914”(association)	0.350
FOSL2	IFT56	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
IRF2BP1	KLHL12	psi-mi:“MI:0914”(association)	0.350

BioGRID (97): IRF2BPL (Affinity Capture-MS), IRF2BPL (Affinity Capture-MS), IRF2BP2 (Co-fractionation), IRF2BPL (Affinity Capture-MS), IRF2BPL (Affinity Capture-MS), IRF2BPL (Affinity Capture-MS), IRF2BPL (Affinity Capture-MS), IRF2BPL (Affinity Capture-MS), IRF2BPL (Affinity Capture-Western), IRF2BPL (Affinity Capture-Western), IRF2BPL (Affinity Capture-Western), IRF2BP2 (Affinity Capture-Western), IRF2BP1 (Affinity Capture-Western), IRF2BPL (Affinity Capture-MS), IRF2BPL (Affinity Capture-MS)

ESM2 similar proteins: A2WY46, A6BLW4, B8A9B2, G0SB31, G4MRQ6, G4N3L5, M2TF54, O54772, O65001, O70132, P17208, P20264, P20265, P20266, P20267, P21952, P25209, P31360, P31361, P53784, P56222, Q01851, Q02516, Q03052, Q0JGS5, Q13164, Q60764, Q60EQ4, Q63262, Q655V5, Q69J40, Q69TW5, Q6EU10, Q75IZ7, Q8L4B2, Q8LCG7, Q8LH59, Q8QZW2, Q92925, Q960X8

Diamond homologs: E9Q1P8, Q1LV17, Q2MJS2, Q5EIC4, Q66IY8, Q6DIH5, Q6NZT6, Q6PCG7, Q7T2G1, Q7Z5L9, Q7ZXS3, Q8IU81, Q8K3X4, Q8R3Y8, Q9H1B7

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
FOXF2	“up-regulates quantity by expression”	IRF2BPL	“transcriptional regulation”
IRF2BPL	“down-regulates quantity by destabilization”	CTNNB1	ubiquitination
IRF2BPL	“up-regulates quantity by expression”	GNRH1	“transcriptional regulation”
IRF2BPL	“down-regulates quantity by repression”	PENK	“transcriptional regulation”
IRF2BPL	“down-regulates quantity by repression”	PDYN	“transcriptional regulation”
Ub:E2	“up-regulates activity”	IRF2BPL	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	44
Uncertain significance	323
Likely benign	105
Benign	20

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013049	NM_024496.4(IRF2BPL):c.2138del (p.Leu713fs)	Pathogenic
1047929	NM_024496.4(IRF2BPL):c.1703_1706dup (p.Trp569Ter)	Pathogenic
1202816	NM_024496.4(IRF2BPL):c.291_322del (p.Gln103fs)	Pathogenic
1675544	NM_024496.4(IRF2BPL):c.516_543del (p.Tyr173fs)	Pathogenic
1679285	NM_024496.4(IRF2BPL):c.1693C>T (p.Gln565Ter)	Pathogenic
1699034	NM_024496.4(IRF2BPL):c.496G>T (p.Glu166Ter)	Pathogenic
1701825	NM_024496.4(IRF2BPL):c.449del (p.Gly150fs)	Pathogenic
1708706	NM_024496.4(IRF2BPL):c.288_319del (p.Ala97fs)	Pathogenic
1802624	NM_024496.4(IRF2BPL):c.2160del (p.Glu720fs)	Pathogenic
1803488	NM_024496.4(IRF2BPL):c.2044C>T (p.Gln682Ter)	Pathogenic
1807567	NM_024496.4(IRF2BPL):c.273_307del (p.Ala92fs)	Pathogenic
1810609	NM_024496.4(IRF2BPL):c.2102del (p.Asn701fs)	Pathogenic
1895461	NM_024496.4(IRF2BPL):c.521_527del (p.Pro174fs)	Pathogenic
2284511	NM_024496.4(IRF2BPL):c.2116_2117delinsT (p.Pro706fs)	Pathogenic
2430009	NM_024496.4(IRF2BPL):c.1846del (p.Ala616fs)	Pathogenic
2507002	NM_024496.4(IRF2BPL):c.475del (p.Ala159fs)	Pathogenic
2525934	NM_024496.4(IRF2BPL):c.1040dup (p.Gln348fs)	Pathogenic
2574800	NM_024496.4(IRF2BPL):c.364C>T (p.Gln122Ter)	Pathogenic
2644420	NM_024496.4(IRF2BPL):c.291_325del (p.Gln103fs)	Pathogenic
2664080	NM_024496.4(IRF2BPL):c.294_325del (p.Gln103fs)	Pathogenic
3343912	NM_024496.4(IRF2BPL):c.1396C>G (p.His466Asp)	Pathogenic
3359041	NM_024496.4(IRF2BPL):c.280_308del (p.Ala94fs)	Pathogenic
3375770	NM_024496.4(IRF2BPL):c.439G>T (p.Glu147Ter)	Pathogenic
3530017	NM_024496.4(IRF2BPL):c.2052delinsAA (p.Pro685fs)	Pathogenic
3731608	NM_024496.4(IRF2BPL):c.1104G>A (p.Trp368Ter)	Pathogenic
3897584	NM_024496.4(IRF2BPL):c.411del (p.Ala138fs)	Pathogenic
3901215	NM_024496.4(IRF2BPL):c.367C>T (p.Gln123Ter)	Pathogenic
4039556	NM_024496.4(IRF2BPL):c.1381G>T (p.Glu461Ter)	Pathogenic
4073670	NM_024496.4(IRF2BPL):c.945del (p.Thr316fs)	Pathogenic
4074734	NM_024496.4(IRF2BPL):c.1787del (p.Pro596fs)	Pathogenic

SpliceAI

55 predictions. Top by Δscore:

Variant	Effect	Δscore
14:77028650:TC:T	donor_gain	0.9200
14:77028651:CT:C	donor_gain	0.8200
14:77028648:A:AC	donor_gain	0.7900
14:77028649:C:CC	donor_gain	0.7900
14:77028657:T:A	donor_gain	0.7800
14:77028554:G:C	donor_gain	0.7700
14:77028617:CG:C	donor_gain	0.7500
14:77028655:G:C	donor_gain	0.6400
14:77028552:A:AC	donor_gain	0.6200
14:77028553:C:CC	donor_gain	0.6200
14:77028291:C:CT	donor_gain	0.5900
14:77028379:C:A	donor_gain	0.5800
14:77028645:G:GC	donor_gain	0.5800
14:77028649:CT:C	donor_gain	0.5700
14:77028076:T:TA	donor_gain	0.5500
14:77028598:C:A	donor_gain	0.5200
14:77028292:C:CT	donor_gain	0.5100
14:77028649:CTCTA:C	donor_gain	0.5100
14:77028035:A:AC	donor_gain	0.4900
14:77028036:C:CC	donor_gain	0.4900
14:77028602:T:TA	donor_gain	0.4800
14:77028622:G:A	donor_gain	0.4500
14:77028548:G:A	donor_gain	0.4400
14:77028332:C:A	donor_gain	0.4200
14:77028031:T:TA	donor_gain	0.4100
14:77028065:AGGCG:A	donor_gain	0.4100
14:77028616:A:AC	donor_gain	0.4100
14:77028617:C:CC	donor_gain	0.4100
14:77028652:T:TT	donor_gain	0.3900
14:77028653:A:AC	donor_gain	0.3900

AlphaMissense

5098 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:77025442:A:G	L784S	1.000
14:77025445:A:C	I783S	1.000
14:77025445:A:G	I783T	1.000
14:77025445:A:T	I783N	1.000
14:77025446:T:A	I783F	1.000
14:77025448:G:A	T782I	1.000
14:77025449:T:G	T782P	1.000
14:77025452:C:G	A781P	1.000
14:77025454:A:C	I780S	1.000
14:77025454:A:G	I780T	1.000
14:77025454:A:T	I780N	1.000
14:77025455:T:A	I780F	1.000
14:77025456:T:A	E779D	1.000
14:77025456:T:G	E779D	1.000
14:77025457:T:A	E779V	1.000
14:77025457:T:C	E779G	1.000
14:77025457:T:G	E779A	1.000
14:77025458:C:G	E779Q	1.000
14:77025458:C:T	E779K	1.000
14:77025461:C:G	G778R	1.000
14:77025465:C:A	M776I	1.000
14:77025465:C:G	M776I	1.000
14:77025465:C:T	M776I	1.000
14:77025466:A:C	M776R	1.000
14:77025466:A:G	M776T	1.000
14:77025466:A:T	M776K	1.000
14:77025468:G:C	F775L	1.000
14:77025468:G:T	F775L	1.000
14:77025469:A:C	F775C	1.000
14:77025469:A:G	F775S	1.000

dbSNP variants (sampled 300 via entrez): RS1000786695 (14:77027999 C>A,T), RS1001341739 (14:77026299 G>C), RS1001376848 (14:77025060 C>T), RS1001678175 (14:77028624 C>T), RS1002213895 (14:77028451 C>T), RS1002403367 (14:77028749 G>A), RS1002484731 (14:77028878 C>T), RS1003474357 (14:77027586 G>A,C), RS1004134960 (14:77029760 G>C), RS1004365753 (14:77028464 C>G,T), RS1005089809 (14:77027623 A>C,T), RS1005559879 (14:77024798 C>T), RS1005694538 (14:77024426 C>T), RS1005762324 (14:77029178 C>T), RS1005806683 (14:77028834 G>A)

Disease associations

OMIM: gene MIM:611720 | disease phenotypes: MIM:618088

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neurodegenerative disease	Definitive	AD

Mondo (5): neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (MONDO:0060759), intellectual disability (MONDO:0001071), autism spectrum disorder (MONDO:0005258), cleft palate (MONDO:0016064), neurodevelopmental disorder (MONDO:0700092)

Orphanet (5): IRF2BPL-related regressive neurodevelopmental disorder-dystonia-seizures syndrome (Orphanet:597623), Cleft palate (Orphanet:2014), Rare genetic intellectual disability (Orphanet:183757), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000565	Esotropia
HP:0000639	Nystagmus
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0002015	Dysphagia
HP:0002059	Cerebral atrophy
HP:0002371	Loss of speech
HP:0002376	Developmental regression
HP:0002403	Positive Romberg sign
HP:0002505	Loss of ambulation
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003676	Progressive
HP:0007371	Corpus callosum atrophy
HP:0011463	Childhood onset
HP:0030319	Weakness of facial musculature

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001431_5	Adverse response to lamotrigine and phenytoin	5.000000e-06
GCST005352_11	Paclitaxel disposition in epithelial ovarian cancer	2.000000e-06
GCST006061_118	Atrial fibrillation	1.000000e-10
GCST006061_193	Atrial fibrillation	2.000000e-09
GCST006414_24	Atrial fibrillation	7.000000e-09
GCST006948_65	Feeling nervous	5.000000e-10
GCST90011898_25	Alanine aminotransferase levels	3.000000e-08
GCST90011899_24	Aspartate aminotransferase levels	3.000000e-09
GCST90013663_88	Alanine aminotransferase levels	4.000000e-10
GCST90013664_53	Aspartate aminotransferase levels	1.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009597	feeling nervous measurement
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
entinostat	increases expression, affects cotreatment	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tretinoin	increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	affects phosphorylation	1
TAK-243	affects sumoylation	1
triphenyl phosphate	affects expression	1
lead acetate	increases expression	1
trichostatin A	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
afimoxifene	decreases expression, decreases reaction	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
AM 251	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Resveratrol	affects cotreatment, increases expression	1
Zoledronic Acid	decreases expression	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Ethanol	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Caffeine	increases phosphorylation	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SS94	HAP1 IRF2BPL (-) 1	Cancer cell line	Male
CVCL_XP85	HAP1 IRF2BPL (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

300 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
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
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
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)