AFF4

Summary

AFF4 (ALF transcription elongation factor 4, HGNC:17869) is a protein-coding gene on chromosome 5q31.1, encoding AF4/FMR2 family member 4 (Q9UHB7). Key component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA.

The protein encoded by this gene belongs to the AF4 family of transcription factors involved in leukemia. It is a component of the positive transcription elongation factor b (P-TEFb) complex. A chromosomal translocation involving this gene and MLL gene on chromosome 11 is found in infant acute lymphoblastic leukemia with ins(5;11)(q31;q31q23).

Source: NCBI Gene 27125 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (Definitive, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 764 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 91
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_014423

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17869
Approved symbol	AFF4
Name	ALF transcription elongation factor 4
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	AF5Q31, MCEF
Ensembl gene	ENSG00000072364
Ensembl biotype	protein_coding
OMIM	604417
Entrez	27125

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000265343, ENST00000378593, ENST00000378595, ENST00000421773, ENST00000425658, ENST00000465484, ENST00000477369, ENST00000478588, ENST00000491831, ENST00000909435, ENST00000944867

RefSeq mRNA: 1 — MANE Select: NM_014423 NM_014423

CCDS: CCDS4164

Canonical transcript exons

ENST00000265343 — 21 exons

Exon	Start	End
ENSE00000762988	132892164	132892404
ENSE00000972460	132896323	132897240
ENSE00000972461	132893030	132893118
ENSE00000972462	132889079	132889173
ENSE00000972463	132888097	132888160
ENSE00000972464	132887846	132887982
ENSE00000972465	132887521	132887592
ENSE00000972466	132886310	132886403
ENSE00000972467	132885076	132885119
ENSE00001084113	132883340	132883560
ENSE00001196195	132875395	132881186
ENSE00001903185	132963259	132963634
ENSE00003511684	132898230	132898392
ENSE00003513110	132934147	132934941
ENSE00003536791	132902442	132902487
ENSE00003575808	132899104	132899141
ENSE00003583237	132937067	132937193
ENSE00003600216	132932178	132932222
ENSE00003617530	132899587	132899641
ENSE00003632595	132927121	132927207
ENSE00003653916	132904368	132904404

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 98.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 53.4828 / max 656.6692, expressed in 1818 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63382	17.2556	1798
63381	15.9956	1785
63379	10.3827	1732
63383	4.4582	1540
63377	1.3184	833
63375	1.0320	680
63384	0.9648	571
63380	0.9292	725
63378	0.8481	502
203683	0.2723	53

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	98.05	gold quality
germinal epithelium of ovary	UBERON:0001304	97.93	gold quality
sperm	CL:0000019	97.85	gold quality
amniotic fluid	UBERON:0000173	97.46	gold quality
adrenal tissue	UBERON:0018303	97.25	gold quality
gingival epithelium	UBERON:0001949	97.11	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.04	gold quality
epithelium of nasopharynx	UBERON:0001951	96.85	gold quality
gingiva	UBERON:0001828	96.82	gold quality
pigmented layer of retina	UBERON:0001782	96.77	gold quality
retina	UBERON:0000966	96.74	gold quality
visceral pleura	UBERON:0002401	96.65	gold quality
parietal pleura	UBERON:0002400	96.52	gold quality
tibia	UBERON:0000979	96.51	gold quality
cauda epididymis	UBERON:0004360	96.47	gold quality
vena cava	UBERON:0004087	96.45	gold quality
corpus epididymis	UBERON:0004359	96.39	gold quality
seminal vesicle	UBERON:0000998	96.19	gold quality
caput epididymis	UBERON:0004358	96.19	gold quality
oral cavity	UBERON:0000167	96.18	gold quality
saphenous vein	UBERON:0007318	95.90	gold quality
pharyngeal mucosa	UBERON:0000355	95.89	gold quality
parotid gland	UBERON:0001831	95.82	gold quality
calcaneal tendon	UBERON:0003701	95.82	gold quality
urethra	UBERON:0000057	95.76	gold quality
superficial temporal artery	UBERON:0001614	95.63	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.47	gold quality
mammary duct	UBERON:0001765	95.41	gold quality
superior surface of tongue	UBERON:0007371	95.40	gold quality
trigeminal ganglion	UBERON:0001675	95.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
ANKRD37
CDKN2A
HNRNPH1
STC2

miRNA regulators (miRDB)

461 targeting AFF4, 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-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-429	100.00	73.44	2698
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833

Literature-anchored findings (GeneRIF, showing 23)

• Data describe the cloning and expression of MCEF, a member of the AF4 family of transcription factors involved in acute lymphoblastic leukemia. [MCEF] (PMID:12065898)
• MCEF has 21 exons & 7 nuclear localization sequence. 3 protein sequences, coded by 3 exons, mediate nuclear localization. Ectopic expression of MCEF repressed HIV-1 LTR-directed RNA polymerase II transcription, at the level of Tat-transactivation. (PMID:17389929)
• AFF4 is required for super elongation complex stability and proper transcription by poised RNA polymerase II. (PMID:20159561)
• Through the bridging functions of Tat and AFF4, P-TEFb and ELL2 combine to form a bifunctional elongation complex that greatly activates HIV-1 transcription. (PMID:20471948)
• overexpression of AFF2/3/4 interferes with the organization and/or biogenesis of nuclear speckles. (PMID:21330300)
• HIV-1 Tat recruits transcription elongation factors dispersed along a flexible AFF4 scaffold. (PMID:23251033)
• AFF4 is positioned to make unexpected direct contacts with HIV Tat, and Tat enhances P-TEFb/CCNT1 affinity for AFF4. (PMID:23471103)
• missense mutations in AFF4 in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that was named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia) (PMID:25730767)
• The TAR central loop contacts the CycT1 Tat-TAR recognition motif (TRM) and the second Tat Zn(2+)-binding loop. Hydrogen-deuterium exchange (HDX) shows that AFF4 helix 2 is stabilized in the TAR complex despite not touching the RNA, explaining how it enhances TAR binding to the SEC 50-fold. (PMID:27731797)
• Study reports the 2.0-A resolution crystal structure of the human ELL2 C-terminal domain bound to its 50-residue binding site on AFF4, the ELLBow. The ELLBow consists of an N-terminal helix followed by an extended hairpin and occupies most of the concave surface of ELL2. This surface is important for the ability of ELL2 to promote HIV-1 Tat-mediated proviral transcription. (PMID:28134250)
• Overexpression of SOX2 rescued the inhibited proliferation, migration, invasion and ALDH activity induced by knockdown of AFF4 in HNSCC cells. (PMID:29741610)
• AFF4 is functionally important target gene of METTL3 in bladder cancer. (PMID:30659266)
• Clinical and molecular spectrum of CHOPS syndrome due to AFF4 mutations has been reported. (PMID:31058441)
• The structure of the conserved AFF protein provides C-terminal homology domain and the molecular basis for the homo- and heterodimerization of AFF proteins. In addition, our data implicate the AFF4-CHD in nucleic acid interactions and identified a conserved loop region as a phosphorylation site for P-TEFb. (PMID:31147444)
• AFF4 enhances odontogenic differentiation of human dental pulp cells. (PMID:32139123)
• Super Elongation Complex as a Targetable Dependency in Diffuse Midline Glioma. (PMID:32268092)
• AFF4 regulates osteogenic differentiation of human dental follicle cells. (PMID:32606293)
• AFF4 facilitates melanoma cell progression by regulating c-Jun activity. (PMID:33417923)
• Distinct roles of two SEC scaffold proteins, AFF1 and AFF4, in regulating RNA polymerase II transcription elongation. (PMID:37528066)
• AFF4 globally affects the release of paused RNA polymerase II in HEL cells. (PMID:37609817)
• AFF4 regulates osteogenic potential of human periodontal ligament stem cells via mTOR-ULK1-autophagy axis. (PMID:37731335)
• The Biological Significance of AFF4: Promoting Transcription Elongation, Osteogenic Differentiation and Tumor Progression. (PMID:37815186)
• N6-methyladenosine-modified circCDK14 promotes ossification of the ligamentum flavum via epigenetic modulation by targeting AFF4. (PMID:39414635)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	aff4	ENSDARG00000001857
mus_musculus	Aff4	ENSMUSG00000049470
rattus_norvegicus	Aff4	ENSRNOG00000006965
drosophila_melanogaster	lilli	FBGN0041111

Paralogs (3): AFF3 (ENSG00000144218), AFF2 (ENSG00000155966), AFF1 (ENSG00000172493)

Protein

Protein identifiers

AF4/FMR2 family member 4 — Q9UHB7 (reviewed: Q9UHB7)

Alternative names: ALL1-fused gene from chromosome 5q31 protein, Major CDK9 elongation factor-associated protein

All UniProt accessions (3): Q9UHB7, C9JCE0, H7C319

UniProt curated annotations — full annotation on UniProt →

Function. Key component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. In the SEC complex, AFF4 acts as a central scaffold that recruits other factors through direct interactions with ELL proteins (ELL, ELL2 or ELL3) and the P-TEFb complex. In case of infection by HIV-1 virus, the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression.

Subunit / interactions. Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3). Interacts with ELL3; the interaction is direct. Interacts with ELL2; the interaction is direct and leads to stabilize ELL2 and prevent ELL2 ubiquitination and degradation.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Ubiquitously expressed. Strongly expressed in heart, placenta, skeletal muscle, pancreas and to a lower extent in brain.

Post-translational modifications. Dephosphorylated at Ser-549 by the PNUTS-PP1 complex, promoting RNA polymerase II transcription pause-release.

Disease relevance. A chromosomal aberration involving AFF4 is found in acute lymphoblastic leukemia (ALL). Insertion ins(5;11)(q31;q13q23) that forms a KMT2A/MLL1-AFF4 fusion protein. CHOPS syndrome (CHOPS) [MIM:616368] A syndrome characterized by cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the AF4 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UHB7-1	1	yes
Q9UHB7-2	2
Q9UHB7-3	3

RefSeq proteins (1): NP_055238* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007797	AF4/FMR2	Family
IPR043639	AF4_int	Conserved_site
IPR043640	AF4/FMR2_CHD	Domain

Pfam: PF05110, PF18875, PF18876

UniProt features (82 total): modified residue 24, compositionally biased region 22, helix 13, sequence variant 5, sequence conflict 5, region of interest 4, splice variant 4, turn 2, chain 1, site 1, cross-link 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
5JW9	X-RAY DIFFRACTION	2
6KN5	X-RAY DIFFRACTION	2.2
6R80	X-RAY DIFFRACTION	2.2
6K7P	X-RAY DIFFRACTION	2.4
4OR5	X-RAY DIFFRACTION	2.9
4IMY	X-RAY DIFFRACTION	2.94
4OGR	X-RAY DIFFRACTION	3
6CYT	X-RAY DIFFRACTION	3.5
5L1Z	X-RAY DIFFRACTION	5.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHB7-F1	54.62	0.18

Functional residue map

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

Catalytic / active sites (1): 350–351 (breakpoint for insertion to form kmt2a/mll1-aff4 fusion protein)

Post-translational modifications (25): 120, 212, 387, 388, 389, 392, 487, 490, 491, 549, 671, 674, 680, 694, 703, 706, 712, 814, 822, 836 …

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-112382	Formation of RNA Pol II elongation complex
R-HSA-674695	RNA Polymerase II Pre-transcription Events
R-HSA-75955	RNA Polymerase II Transcription Elongation
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 586 (showing top): ATF_B, TGGTGCT_MIR29A_MIR29B_MIR29C, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, TGCGCANK_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, TGCACTT_MIR519C_MIR519B_MIR519A, TTTGTAG_MIR520D, TATTATA_MIR374, GTTAAAG_MIR302B, CREBP1_Q2, GOBP_MALE_GAMETE_GENERATION, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GTGCCTT_MIR506

GO Biological Process (3): spermatid development (GO:0007286), regulation of gene expression (GO:0010468), response to endoplasmic reticulum stress (GO:0034976)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (8): euchromatin (GO:0000791), fibrillar center (GO:0001650), nucleoplasm (GO:0005654), transcription elongation factor complex (GO:0008023), nuclear body (GO:0016604), super elongation complex (GO:0032783), nucleus (GO:0005634), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
RNA Polymerase II Transcription	2
RNA Polymerase II Transcription Elongation	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
nucleoplasm	2
intracellular membraneless organelle	2
germ cell development	1
spermatid differentiation	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cellular response to stress	1
binding	1
chromatin	1
nucleolus	1
nuclear lumen	1
nuclear protein-containing complex	1
transcription elongation factor complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2094 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AFF4	ELL2	O00472	997
AFF4	ELL	P55199	997
AFF4	MLLT1	Q03111	995
AFF4	CCNT1	O60563	994
AFF4	MLLT3	P42568	994
AFF4	CDK9	P50750	989
AFF4	AFF1	P51825	985
AFF4	CCNT2	O60583	946
AFF4	ELL3	Q9HB65	924
AFF4	KMT2A	Q03164	824
AFF4	LARP7	Q4G0J3	795
AFF4	MEPCE	Q7L2J0	778
AFF4	DOT1L	Q8TEK3	710
AFF4	RBM8A	Q9Y5S9	682
AFF4	HEXIM1	O94992	678

IntAct

144 interactions, top by confidence:

A	B	Type	Score
CDK9	CCNT1	psi-mi:“MI:0914”(association)	0.980
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
EAF1	ELL2	psi-mi:“MI:0914”(association)	0.840
AFF4	CCNT1	psi-mi:“MI:0914”(association)	0.810
CCNT1	AFF4	psi-mi:“MI:0915”(physical association)	0.810
AFF4	MLLT1	psi-mi:“MI:0915”(physical association)	0.760
AFF4	MLLT1	psi-mi:“MI:0914”(association)	0.760
AFF4	ELL2	psi-mi:“MI:0914”(association)	0.730
CDK9	AIP	psi-mi:“MI:0914”(association)	0.730
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
MED26	MED19	psi-mi:“MI:0914”(association)	0.730
MLLT3	CDK9	psi-mi:“MI:0914”(association)	0.730
MLLT1	DOT1L	psi-mi:“MI:0914”(association)	0.680
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
MLLT1	ELL2	psi-mi:“MI:0914”(association)	0.640

BioGRID (233): AFF4 (Two-hybrid), AFF4 (Two-hybrid), AFF4 (Two-hybrid), AFF4 (Two-hybrid), AFF4 (Two-hybrid), AFF4 (Affinity Capture-MS), AFF4 (Affinity Capture-MS), CDK9 (Affinity Capture-MS), ELL2 (Affinity Capture-MS), EAF2 (Affinity Capture-MS), HEXIM1 (Affinity Capture-MS), ELL3 (Affinity Capture-MS), CCNT2 (Affinity Capture-MS), CCNT1 (Affinity Capture-MS), ELL (Affinity Capture-MS)

ESM2 similar proteins: A0P8Z5, A2AJT4, A6NNA2, A7MD48, F1LR10, O88573, P0CB65, P51825, P51826, P51827, Q14241, Q2KJH5, Q2T9Y0, Q569Z6, Q5BJ39, Q5M7V8, Q5PPJ2, Q5RD75, Q5T6C5, Q5VUA4, Q63187, Q6QZN6, Q6ZPR1, Q80WV7, Q80Z37, Q8BKA3, Q8BM65, Q8BTI8, Q8BZX4, Q8CB77, Q8K019, Q8TF01, Q93075, Q96B23, Q96IZ7, Q96RL1, Q99PP2, Q9BW71, Q9DBU6, Q9ERQ3

Diamond homologs: B3MLB7, B3NAM7, B4JQ42, B4KFE1, B4LV24, B4MUE1, B4NXA8, O55112, P51816, P51826, P51827, Q29KG4, Q7YQM1, Q7YQM2, Q9ESC8, Q9UHB7, Q9VQI9, P51825, O88573

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AFF4	“form complex”	“AEP complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 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
Formation of RNA Pol II elongation complex	9	22.3×	4e-08
RNA Polymerase II Transcription Elongation	9	22.3×	4e-08
HIV elongation arrest and recovery	5	22.2×	2e-04
Pausing and recovery of HIV elongation	5	22.2×	2e-04
RNA Polymerase II Pre-transcription Events	10	17.6×	4e-08
Formation of HIV elongation complex in the absence of HIV Tat	5	15.9×	5e-04
RNA polymerase II transcribes snRNA genes	8	15.8×	5e-06
Transcription of the HIV genome	6	13.3×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	9	28.5×	2e-08
transcription elongation by RNA polymerase II	6	28.0×	3e-05
RNA polymerase II preinitiation complex assembly	5	14.3×	6e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — HCC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	421
Likely benign	235
Benign	49

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1527198	GRCh37/hg19 5q31.1-31.2(chr5:132031902-137623639)	Pathogenic
190329	NM_014423.4(AFF4):c.760A>G (p.Thr254Ala)	Pathogenic
58360	GRCh38/hg38 5q31.1(chr5:132816203-135383158)x1	Pathogenic
1698778	NM_014423.4(AFF4):c.778A>G (p.Met260Val)	Likely pathogenic
3766957	NM_014423.4(AFF4):c.767A>C (p.Tyr256Ser)	Likely pathogenic

SpliceAI

3681 predictions. Top by Δscore:

Variant	Effect	Δscore
5:132881078:T:TA	donor_gain	1.0000
5:132883335:CCTA:C	donor_gain	1.0000
5:132883337:TA:T	donor_loss	1.0000
5:132883556:CTTTG:C	acceptor_gain	1.0000
5:132883557:TTTG:T	acceptor_gain	1.0000
5:132883558:TTG:T	acceptor_gain	1.0000
5:132883559:TG:T	acceptor_gain	1.0000
5:132883561:C:CC	acceptor_gain	1.0000
5:132885118:TT:T	acceptor_gain	1.0000
5:132885120:C:CC	acceptor_gain	1.0000
5:132886307:TA:T	donor_loss	1.0000
5:132886308:A:AC	donor_gain	1.0000
5:132886308:A:C	donor_loss	1.0000
5:132886308:AC:A	donor_gain	1.0000
5:132886309:C:CG	donor_gain	1.0000
5:132886309:CC:C	donor_gain	1.0000
5:132886309:CCT:C	donor_gain	1.0000
5:132886309:CCTT:C	donor_gain	1.0000
5:132886404:C:CC	acceptor_gain	1.0000
5:132886409:C:T	acceptor_gain	1.0000
5:132886409:CAA:C	acceptor_gain	1.0000
5:132886410:A:T	acceptor_gain	1.0000
5:132887519:A:AC	donor_gain	1.0000
5:132887520:C:CC	donor_gain	1.0000
5:132887838:CCACT:C	donor_loss	1.0000
5:132887839:CACTT:C	donor_loss	1.0000
5:132887840:ACTT:A	donor_loss	1.0000
5:132887841:CTTA:C	donor_loss	1.0000
5:132887842:TTACT:T	donor_loss	1.0000
5:132887843:TAC:T	donor_loss	1.0000

AlphaMissense

7683 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:132881105:C:G	R1149P	1.000
5:132883367:C:G	A1113P	1.000
5:132886326:A:G	L1028P	1.000
5:132887852:A:G	L976P	1.000
5:132887922:C:A	G953W	1.000
5:132887946:C:G	A945P	1.000
5:132888107:G:T	A929E	1.000
5:132888115:C:A	K926N	1.000
5:132888115:C:G	K926N	1.000
5:132897199:C:A	W477C	1.000
5:132897199:C:G	W477C	1.000
5:132897214:C:A	W472C	1.000
5:132897214:C:G	W472C	1.000
5:132897216:A:G	W472R	1.000
5:132897216:A:T	W472R	1.000
5:132934289:G:T	P259H	1.000
5:132934290:G:A	P259S	1.000
5:132934290:G:T	P259T	1.000
5:132934293:G:C	R258G	1.000
5:132934299:A:G	Y256H	1.000
5:132934301:G:T	A255D	1.000
5:132934898:A:G	L56P	1.000
5:132934910:A:C	I52S	1.000
5:132934913:C:G	R51P	1.000
5:132934922:A:G	L48S	1.000
5:132934929:C:G	D46H	1.000
5:132937140:C:G	R17P	1.000
5:132937162:G:T	R10S	1.000
5:132881087:A:G	L1155P	0.999
5:132881096:A:G	L1152P	0.999

dbSNP variants (sampled 300 via entrez): RS1000076965 (5:132883955 A>G), RS1000089191 (5:132932026 G>A), RS1000139590 (5:132886072 G>A,C), RS1000147134 (5:132882243 A>C), RS1000149385 (5:132928727 T>A), RS1000157431 (5:132904246 A>T), RS1000230019 (5:132944838 G>A), RS1000253393 (5:132893959 T>C), RS1000274924 (5:132950239 G>A), RS1000301160 (5:132903920 A>C,G), RS1000305458 (5:132955354 C>T), RS1000400299 (5:132909931 G>A), RS1000407890 (5:132959294 G>C), RS1000416604 (5:132955549 C>T), RS1000478472 (5:132918919 T>A,C)

Disease associations

OMIM: gene MIM:604417 | disease phenotypes: MIM:616368, MIM:620568

GenCC curated gene-disease

Disease	Classification	Inheritance
cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Definitive	Autosomal dominant

Mondo (5): cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (MONDO:0014609), autism spectrum disorder (MONDO:0005258), dilated cardiomyopathy (MONDO:0005021), Cornelia de Lange syndrome 6 (MONDO:0957921), coloboma (MONDO:0001476)

Orphanet (4): Cognitive impairment-coarse facies-heart defects-obesity-pulmonary involvement-short stature-skeletal dysplasia syndrome (Orphanet:444077), Dilated cardiomyopathy (Orphanet:217604), OBSOLETE: Ocular coloboma (Orphanet:194), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

91 total (30 of 91 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000158	Macroglossia
HP:0000162	Glossoptosis
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000293	Full cheeks
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000378	Cupped ear
HP:0000391	Thickened helices
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000410	Mixed hearing impairment
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000520	Proptosis

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST004861_71	Itch intensity from mosquito bite	5.000000e-07
GCST004862_159	Itch intensity from mosquito bite adjusted by bite size	2.000000e-06
GCST004865_22	Itch intensity from mosquito bite adjusted by bite size	1.000000e-07
GCST008058_133	Estimated glomerular filtration rate	1.000000e-15
GCST008059_20	Estimated glomerular filtration rate	2.000000e-15
GCST008916_34	Asthma	2.000000e-09
GCST90020024_919	A body shape index	2.000000e-11
GCST90020029_1276	Waist circumference adjusted for body mass index	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D003103	Coloboma	C11.250.110; C11.270.147; C16.131.384.282

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724734 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

5 potent at pChembl≥5 of 5 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.91	Kd	12.24	nM	CHEMBL5653589
7.91	ED50	12.24	nM	CHEMBL5653589
7.07	Kd	85	nM	MOLIBRESIB
7.05	Kd	89	nM	MOLIBRESIB
7.00	IC50	100	nM	MOLIBRESIB

PubChem BioAssay actives

4 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147814: Binding affinity to human AFF4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0122	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179172: Binding affinity against AFF4 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0850	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, increases expression, affects expression	4
Benzo(a)pyrene	increases methylation, decreases expression, increases expression	3
Aflatoxin B1	decreases methylation, increases expression, increases methylation	3
bisphenol A	increases methylation, affects cotreatment, decreases expression	2
sodium arsenite	increases expression, increases stability	2
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	2
(+)-JQ1 compound	affects binding, decreases reaction, increases reaction	2
Acetaminophen	increases expression	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Formaldehyde	decreases expression, increases expression	2
Ozone	increases oxidation, increases abundance, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	decreases expression, increases methylation	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
geraniol	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
coumarin	decreases phosphorylation	1
1-nitropyrene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650856	Binding	Binding affinity to human AFF4 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_7984	KP-L-RY	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder