MSL2

Summary

MSL2 (MSL complex subunit 2, HGNC:25544) is a protein-coding gene on chromosome 3q22.3, encoding E3 ubiquitin-protein ligase MSL2 (Q9HCI7). Non-catalytic component of the MSL histone acetyltransferase complex, a multiprotein complex that mediates the majority of histone H4 acetylation at ‘Lys-16’ (H4K16ac), an epigenetic mark that prevents chromatin compaction.

Enables histone H2B ubiquitin ligase activity. Involved in DNA damage response and protein monoubiquitination. Located in nucleus. Part of MSL complex. Is active in chromatin.

Source: NCBI Gene 55167 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Karayol-Borroto-Haghshenas neurodevelopmental syndrome (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 45
• Clinical variants (ClinVar): 102 total — 7 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 125
• MANE Select transcript: NM_018133

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25544
Approved symbol	MSL2
Name	MSL complex subunit 2
Location	3q22.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10546, KIAA1585, msl-2
Ensembl gene	ENSG00000174579
Ensembl biotype	protein_coding
OMIM	614802
Entrez	55167

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 8 protein_coding

ENST00000309993, ENST00000434835, ENST00000473093, ENST00000481989, ENST00000491050, ENST00000703103, ENST00000703104, ENST00000703105

RefSeq mRNA: 2 — MANE Select: NM_018133 NM_001145417, NM_018133

CCDS: CCDS33861, CCDS46922

Canonical transcript exons

ENST00000309993 — 2 exons

Exon	Start	End
ENSE00001246581	136194972	136196335
ENSE00001845408	136148917	136152738

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 94.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.1109 / max 219.3551, expressed in 1785 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44728	6.8584	1712
44727	3.9988	1294
44725	2.6209	996
44729	1.3066	539
44724	0.6769	108
44730	0.5995	99
44721	0.5358	93
44722	0.2629	114
44726	0.1299	38
44723	0.1212	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	94.32	gold quality
ventricular zone	UBERON:0003053	93.28	gold quality
ganglionic eminence	UBERON:0004023	91.77	gold quality
leukocyte	CL:0000738	90.14	gold quality
cortical plate	UBERON:0005343	90.14	gold quality
monocyte	CL:0000576	90.02	gold quality
mononuclear cell	CL:0000842	89.91	gold quality
lymph node	UBERON:0000029	89.83	gold quality
thymus	UBERON:0002370	89.05	gold quality
bone marrow cell	CL:0002092	88.60	gold quality
bone marrow	UBERON:0002371	88.54	gold quality
granulocyte	CL:0000094	88.31	gold quality
blood	UBERON:0000178	87.37	gold quality
vermiform appendix	UBERON:0001154	87.12	gold quality
embryo	UBERON:0000922	86.44	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.21	gold quality
islet of Langerhans	UBERON:0000006	86.15	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	86.01	gold quality
calcaneal tendon	UBERON:0003701	85.97	gold quality
caecum	UBERON:0001153	85.70	gold quality
cranial nerve II	UBERON:0000941	85.32	gold quality
tonsil	UBERON:0002372	85.15	gold quality
spleen	UBERON:0002106	84.82	gold quality
colonic epithelium	UBERON:0000397	84.75	gold quality
adrenal tissue	UBERON:0018303	84.72	gold quality
choroid plexus epithelium	UBERON:0003911	84.67	gold quality
gall bladder	UBERON:0002110	84.36	gold quality
lower lobe of lung	UBERON:0008949	84.27	gold quality
cerebellar vermis	UBERON:0004720	84.24	gold quality
rectum	UBERON:0001052	84.13	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.91
E-CURD-112	no	1.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

177 targeting MSL2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4778-3P	99.93	70.40	1818

Literature-anchored findings (GeneRIF, showing 7)

• A multisubunit human histone acetylase complex that contains homologs of the Drosophila MSL proteins MOF, MSL1 (hampin A), MSL2, and MSL3 was described. This complex is responsible for histone H4 lysine-16 acetylation of all cellular chromosomes. (PMID:16227571)
• MSL2, together with MSL1, has robust histone ubiquitylation activity that mainly targets nucleosomal H2B on lysine 34. (PMID:21726816)
• Msl2 is a novel component of the vertebrate DNA damage response. (PMID:23874665)
• HBx-elevated MSL2 modulates hepatitis B virus (HBV) cccDNA in hepatoma cells to promote hepatocarcinogenesis, forming a positive feedback loop of HBx/MSL2/cccDNA/HBV. (PMID:28608964)
• MALAT-1 directly induced MSL2 expression in Myasthenia gravis (MG) by acting as a competing endogenous RNA for miR-338-3p, suggesting that it may serve as a therapeutic target for MG treatment. (PMID:30362606)
• Novel protein-truncating variants of a chromatin-modifying gene MSL2 in syndromic neurodevelopmental disorders. (PMID:38702431)
• MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature. (PMID:38815585)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	msl2a	ENSDARG00000038909
danio_rerio	msl2b	ENSDARG00000039430
mus_musculus	Msl2	ENSMUSG00000066415
rattus_norvegicus	Msl2	ENSRNOG00000023021
drosophila_melanogaster	msl-2	FBGN0005616

Protein

Protein identifiers

E3 ubiquitin-protein ligase MSL2 — Q9HCI7 (reviewed: Q9HCI7)

Alternative names: Male-specific lethal 2-like 1, Male-specific lethal-2 homolog, Male-specific lethal-2 homolog 1, RING finger protein 184

All UniProt accessions (5): Q9HCI7, A0A8V8TR57, C9IZ03, C9IZG7, C9J5S2

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the MSL histone acetyltransferase complex, a multiprotein complex that mediates the majority of histone H4 acetylation at ‘Lys-16’ (H4K16ac), an epigenetic mark that prevents chromatin compaction. The MSL complex is required for chromosome stability and genome integrity by maintaining homeostatic levels of H4K16ac. The MSL complex is also involved in gene dosage by promoting up-regulation of genes expressed by the X chromosome. X up-regulation is required to compensate for autosomal biallelic expression. The MSL complex also participates in gene dosage compensation by promoting expression of Tsix non-coding RNA. MSL2 plays a key role in gene dosage by ensuring biallelic expression of a subset of dosage-sensitive genes, including many haploinsufficient genes. Acts by promoting promoter-enhancer contacts, thereby preventing DNA methylation of one allele and creating a methylation-free environment for methylation-sensitive transcription factors such as SP1, KANSL1 and KANSL3. Also acts as an E3 ubiquitin ligase that promotes monoubiquitination of histone H2B at ‘Lys-35’ (H2BK34Ub), but not that of H2A. This activity is greatly enhanced by heterodimerization with MSL1. H2B ubiquitination in turn stimulates histone H3 methylation at ‘Lys-4’ (H3K4me) and ‘Lys-79’ (H3K79me) and leads to gene activation, including that of HOXA9 and MEIS1. Also involved in the DNA damage response by mediating ubiquitination of TP53/p53 and TP53BP1.

Subunit / interactions. Component of a multisubunit histone acetyltransferase complex (MSL) at least composed of the KAT8/MOF/MYST1, MSL1/hampin, MSL2 and MSL3. Forms a MSL heterotetrameric core with MSL1.

Subcellular location. Nucleus. Chromosome.

Disease relevance. Karayol-Borroto-Haghshenas neurodevelopmental syndrome (KBHS) [MIM:620985] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, intellectual disability, psychiatric manifestations including autism spectrum disorder and attention deficit, dysmorphic features, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the MSL2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HCI7-1	1	yes
Q9HCI7-2	2

RefSeq proteins (2): NP_001138889, NP_060603* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR032043	Msl2_Znf-RING	Domain
IPR032049	Msl2-CXC	Domain
IPR033467	Tesmin/TSO1-like_CXC	Domain
IPR037922	MSL2	Family

Pfam: PF16682, PF16685

UniProt features (44 total): binding site 20, sequence variant 4, helix 4, region of interest 2, sequence conflict 2, turn 2, strand 2, chain 1, domain 1, zinc finger region 1, modified residue 1, cross-link 1, splice variant 1, mutagenesis site 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4B7Y	X-RAY DIFFRACTION	3.25
4B86	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCI7-F1	56.58	0.17

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 (20): 67; 70; 81; 84; 462; 462; 464; 476; 476; 481; 483; 490 …

Post-translational modifications (2): 447, 375

Mutagenesis-validated functional residues (1):

Position	Phenotype
64	great reduction in h2b ubiquitination. no effect on msl1-binding.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-3214847	HATs acetylate histones
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization

MSigDB gene sets: 502 (showing top): RNGTGGGC_UNKNOWN, TGCGCANK_UNKNOWN, TTTGTAG_MIR520D, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, AAGCCAT_MIR135A_MIR135B, AATGGAG_MIR136, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GTGTTGA_MIR505, GOBP_PROTEIN_MONOUBIQUITINATION, ZIC1_01, GOBP_DNA_DAMAGE_RESPONSE, PYEON_CANCER_HEAD_AND_NECK_VS_CERVICAL_UP, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, ATGCTGG_MIR338

GO Biological Process (6): protein monoubiquitination (GO:0006513), DNA damage response (GO:0006974), protein ubiquitination (GO:0016567), epigenetic regulation of gene expression (GO:0040029), positive regulation of DNA-templated transcription (GO:0045893), chromatin organization (GO:0006325)

GO Molecular Function (7): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), promoter-enhancer loop anchoring activity (GO:0140585), histone H2B ubiquitin ligase activity (GO:0141054), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), MSL complex (GO:0072487), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Chromatin organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein ubiquitination	1
cellular response to stress	1
protein modification by small protein conjugation	1
chromatin remodeling	1
regulation of gene expression	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
cellular component organization	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
chromatin loop anchoring activity	1
histone ubiquitin ligase activity	1
binding	1
catalytic activity	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
H4 histone acetyltransferase complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1454 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MSL2	MSL3	Q8N5Y2	999
MSL2	MSL1	Q68DK7	972
MSL2	TIA1	P31483	808
MSL2	KAT8	Q9H7Z6	644
MSL2	CSDE1	O75534	601
MSL2	TGFBI	Q15582	529
MSL2	H4C7	Q99525	526
MSL2	H4C16	P02304	501
MSL2	RCHY1	Q96PM5	481
MSL2	SMC5	Q8IY18	477
MSL2	FAS	P25445	469
MSL2	RPL32	P02433	460
MSL2	DHX9	Q08211	452
MSL2	KANSL2	Q9H9L4	450
MSL2	NUP160	Q12769	447

IntAct

32 interactions, top by confidence:

A	B	Type	Score
MSL3	MSL1	psi-mi:“MI:0914”(association)	0.760
MSL1	MSL2	psi-mi:“MI:0915”(physical association)	0.670
KAT8	MSL1	psi-mi:“MI:0914”(association)	0.640
YY1	YY2	psi-mi:“MI:0914”(association)	0.570
MSL2	HBB	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
MSL2	NHLRC2	psi-mi:“MI:0915”(physical association)	0.400
Kat8	PHF20L1	psi-mi:“MI:0915”(physical association)	0.400
TRIM8	MSL2	psi-mi:“MI:0915”(physical association)	0.370
Kat8	HCFC1	psi-mi:“MI:0914”(association)	0.350
Mis12	CTNNB1	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
MSL2	IGHG2	psi-mi:“MI:0914”(association)	0.350
MSL3	TUBA1B	psi-mi:“MI:0914”(association)	0.350
KAT8	HCFC1	psi-mi:“MI:0914”(association)	0.350
KAT8	MSL3B	psi-mi:“MI:0914”(association)	0.350
H2BC21	SMCHD1	psi-mi:“MI:0914”(association)	0.350
AGGF1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
SF3B4	MED19	psi-mi:“MI:2364”(proximity)	0.270
XRCC6	PSMD11	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
ZRANB2	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
	MSL2	psi-mi:“MI:0915”(physical association)	0.000
MSL2	YWHAE	psi-mi:“MI:0915”(physical association)	0.000
YWHAG	MSL2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (70): MSL2 (Affinity Capture-MS), MSL2 (Affinity Capture-MS), MSL1 (Affinity Capture-MS), KAT8 (Affinity Capture-MS), MSL3 (Affinity Capture-MS), HBB (Affinity Capture-MS), HBA2 (Affinity Capture-MS), IGHG2 (Affinity Capture-MS), MSL2 (Affinity Capture-RNA), MSL2 (Affinity Capture-Western), MSL2 (Reconstituted Complex), APOBEC3B (Biochemical Activity), MSL2 (Affinity Capture-MS), MSL2 (Affinity Capture-MS), MSL2 (Proximity Label-MS)

ESM2 similar proteins: A0A0R4IYX6, A0A1D5NVS8, A0A1L8H0H2, A0AVK6, A5GFT6, A7XYH5, A7XYJ6, B7ZS37, B8A5Y1, D4A666, E1B7L7, E1BKK0, E1BLP6, F1LMN3, F6YVB9, F8VPJ6, Q12766, Q13029, Q14B70, Q2HNT1, Q2HNT2, Q2KHR2, Q4V9H5, Q58FA4, Q5DTH5, Q5ZIE8, Q5ZIX8, Q5ZJ69, Q5ZM88, Q63679, Q63755, Q68FE9, Q69ZF8, Q6DRC5, Q6P4F7, Q6PCM1, Q6ZSZ6, Q76L83, Q80Y19, Q8BHZ4

Diamond homologs: A0A1D5NVS8, P50534, Q69ZF8, Q9HCI7

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MSL2	“form complex”	“MSL acetyltransferase”	binding
MSL2	“down-regulates activity”	TP53	ubiquitination
MSL2	“down-regulates activity”	H2BC21	monoubiquitination

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.

Reactome pathways:

Pathway	Partners	Fold	FDR
HATs acetylate histones	5	16.5×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
chromatin remodeling	5	12.6×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	5
Uncertain significance	73
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
2265934	NM_018133.4(MSL2):c.521dup (p.Leu174fs)	Pathogenic
2475601	NM_018133.4(MSL2):c.535G>T (p.Glu179Ter)	Pathogenic
2581153	NM_018133.4(MSL2):c.67G>T (p.Gly23Ter)	Pathogenic
3363109	MSL2, 4-BP DEL, 694TCTG	Pathogenic
3702150	NM_018133.4(MSL2):c.1479T>A (p.Cys493Ter)	Pathogenic
3902836	NM_018133.4(MSL2):c.119A>G (p.Gln40Arg)	Pathogenic
4712122	NM_018133.4(MSL2):c.1A>G (p.Met1Val)	Pathogenic
3773655	NM_018133.4(MSL2):c.1209_1210insAGTAA (p.Thr405fs)	Likely pathogenic
3781134	NM_018133.4(MSL2):c.1378_1381del (p.Lys460fs)	Likely pathogenic
3901175	NM_018133.4(MSL2):c.1231_1232del (p.Ser411_His412insTer)	Likely pathogenic
3901874	NM_018133.4(MSL2):c.1290dup (p.Asp431fs)	Likely pathogenic
3901875	NM_018133.4(MSL2):c.1024C>T (p.Arg342Ter)	Likely pathogenic

SpliceAI

650 predictions. Top by Δscore:

Variant	Effect	Δscore
3:136158533:T:A	donor_gain	1.0000
3:136152875:T:C	donor_gain	0.9900
3:136152958:T:TA	donor_gain	0.9900
3:136152595:A:C	donor_gain	0.9800
3:136152735:TGTC:T	acceptor_gain	0.9800
3:136152737:TCCT:T	acceptor_loss	0.9800
3:136152739:C:CC	acceptor_gain	0.9800
3:136152740:T:A	acceptor_loss	0.9800
3:136152850:A:AC	donor_gain	0.9800
3:136152851:C:CC	donor_gain	0.9800
3:136194966:TCTCA:T	donor_loss	0.9800
3:136194967:CTCA:C	donor_loss	0.9800
3:136194968:TCACC:T	donor_loss	0.9800
3:136194969:CA:C	donor_loss	0.9800
3:136194970:A:AC	donor_gain	0.9800
3:136194970:ACCGC:A	donor_loss	0.9800
3:136194971:C:CC	donor_gain	0.9800
3:136194971:C:CG	donor_loss	0.9800
3:136152665:G:A	donor_gain	0.9700
3:136152880:G:C	donor_gain	0.9700
3:136194965:GTCTC:G	donor_loss	0.9700
3:136194971:CCG:C	donor_gain	0.9700
3:136152851:CTAGA:C	donor_gain	0.9600
3:136158509:A:AC	donor_gain	0.9600
3:136158510:C:CC	donor_gain	0.9600
3:136158514:A:C	donor_gain	0.9600
3:136194964:CGTCT:C	donor_loss	0.9600
3:136152905:G:C	donor_gain	0.9500
3:136195326:TCCAG:T	donor_gain	0.9500
3:136152737:TC:T	acceptor_gain	0.9400

AlphaMissense

3795 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:136151307:A:G	L525P	1.000
3:136151340:G:T	A514D	1.000
3:136151342:A:C	F513L	1.000
3:136151342:A:T	F513L	1.000
3:136151343:A:C	F513C	1.000
3:136151343:A:G	F513S	1.000
3:136151344:A:G	F513L	1.000
3:136151352:A:G	L510P	1.000
3:136151356:T:C	K509E	1.000
3:136151357:C:A	K508N	1.000
3:136151357:C:G	K508N	1.000
3:136151364:C:A	G506V	1.000
3:136151364:C:T	G506E	1.000
3:136151365:C:A	G506W	1.000
3:136151365:C:G	G506R	1.000
3:136151365:C:T	G506R	1.000
3:136151372:C:A	M503I	1.000
3:136151372:C:G	M503I	1.000
3:136151372:C:T	M503I	1.000
3:136151377:A:C	Y502D	1.000
3:136151379:G:A	S501F	1.000
3:136151381:G:C	N500K	1.000
3:136151381:G:T	N500K	1.000
3:136151382:T:A	N500I	1.000
3:136151383:T:C	N500D	1.000
3:136151387:G:C	C498W	1.000
3:136151388:C:A	C498F	1.000
3:136151388:C:G	C498S	1.000
3:136151388:C:T	C498Y	1.000
3:136151389:A:G	C498R	1.000

dbSNP variants (sampled 300 via entrez): RS1000107355 (3:136148783 C>T), RS1000161508 (3:136179566 T>G), RS1000170226 (3:136174728 T>C), RS1000201232 (3:136174877 T>C), RS1000232217 (3:136148533 C>T), RS1000253338 (3:136180484 G>A), RS1000278907 (3:136179555 T>C), RS1000305405 (3:136167337 T>C), RS1000321822 (3:136188748 T>A,G), RS1000350189 (3:136172461 T>A,C), RS1000496759 (3:136168790 T>A,C), RS1000541914 (3:136175969 A>C,T), RS1000546156 (3:136186912 G>A), RS1000652228 (3:136173307 G>A), RS1000786386 (3:136191793 C>A,G,T)

Disease associations

OMIM: gene MIM:614802 | disease phenotypes: MIM:209850, MIM:620985

GenCC curated gene-disease

Disease	Classification	Inheritance
Karayol-Borroto-Haghshenas neurodevelopmental syndrome	Definitive	Autosomal dominant
complex neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (3): autism (MONDO:0005260), Karayol-Borroto-Haghshenas neurodevelopmental syndrome (MONDO:0975836), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

125 total (30 of 125 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000098	Tall stature
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000289	Broad philtrum
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000325	Triangular face
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000465	Webbed neck
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000518	Cataract
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000568	Microphthalmia
HP:0000577	Exotropia

GWAS associations

45 associations (top):

Study	Trait	p-value
GCST000758_5	Triglycerides	3.000000e-08
GCST002147_16	Fibrinogen	1.000000e-16
GCST002216_38	Triglycerides	2.000000e-12
GCST002539_50	Schizophrenia	7.000000e-11
GCST002897_30	Triglycerides	8.000000e-09
GCST002899_24	HDL cholesterol	4.000000e-10
GCST003681_11	C-reactive protein levels or triglyceride levels (pleiotropy)	5.000000e-11
GCST004237_49	Triglyceride levels	2.000000e-12
GCST004521_157	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004946_94	Schizophrenia	4.000000e-15
GCST005196_110	Coronary artery disease	1.000000e-08
GCST005998_9	Alanine transaminase levels	4.000000e-08
GCST006803_84	Schizophrenia	4.000000e-12
GCST007615_17	C-reactive protein levels	3.000000e-10
GCST007930_82	Medication use (agents acting on the renin-angiotensin system)	5.000000e-08
GCST007931_19	Medication use (HMG CoA reductase inhibitors)	2.000000e-10
GCST008053_182	Height	2.000000e-07
GCST008053_77	Height	6.000000e-10
GCST008058_238	Estimated glomerular filtration rate	8.000000e-14
GCST008059_45	Estimated glomerular filtration rate	8.000000e-14
GCST008062_53	Blood urea nitrogen levels	5.000000e-21
GCST008074_116	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-12
GCST008074_142	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	6.000000e-13
GCST008075_119	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-14
GCST008075_38	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	9.000000e-17
GCST008078_48	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	7.000000e-06
GCST008079_75	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-06
GCST008083_111	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-13
GCST008083_160	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	7.000000e-14
GCST008084_189	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	4.000000e-16

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004458	C-reactive protein measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0006925	lipoprotein A measurement
EFO:0007993	lymphocyte percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
testosterone enanthate	affects expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
jinfukang	decreases expression	1
Arsenic Trioxide	increases response to substance	1
Fulvestrant	increases methylation	1
Acetaminophen	increases expression	1
Benzene	increases expression	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Endosulfan	decreases expression	1
Formaldehyde	decreases expression	1
Testosterone	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1
Lactic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With 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
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
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
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms