MPP3

Summary

MPP3 (MAGUK p55 scaffold protein 3, HGNC:7221) is a protein-coding gene on chromosome 17q21.31, encoding MAGUK p55 subfamily member 3 (Q13368). Participates in cell spreading through the phosphoinositide-3-kinase (PI3K) pathway by connecting CADM1 to DLG1 and the regulatory subunit of phosphoinositide-3-kinase (PI3K). It is haploinsufficient (ClinGen: sufficient evidence).

This gene product is a member of a family of membrane-associated proteins termed MAGUKs (membrane-associated guanylate kinase homologs). MAGUKs interact with the cytoskeleton and regulate cell proliferation, signaling pathways, and intracellular junctions. This protein contains a conserved sequence, called the SH3 (src homology 3) motif, found in several other proteins that associate with the cytoskeleton and are suspected to play important roles in signal transduction. Alternatively spliced transcript variants have been identified. One transcript variant is experimentally supported, but it doesn’t encode a protein.

Source: NCBI Gene 4356 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic X-linked intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 481 total — 22 pathogenic, 18 likely-pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001932

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7221
Approved symbol	MPP3
Name	MAGUK p55 scaffold protein 3
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000161647
Ensembl biotype	protein_coding
OMIM	601114
Entrez	4356

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 4 retained_intron, 3 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000398389, ENST00000398393, ENST00000466083, ENST00000475450, ENST00000479797, ENST00000480958, ENST00000486600, ENST00000496503, ENST00000589375, ENST00000908431

RefSeq mRNA: 3 — MANE Select: NM_001932 NM_001330233, NM_001353080, NM_001932

CCDS: CCDS42344, CCDS82135

Canonical transcript exons

ENST00000398389 — 20 exons

Exon	Start	End
ENSE00001404140	43832761	43832819
ENSE00001533023	43800811	43801877
ENSE00001533045	43816677	43816697
ENSE00003459922	43827751	43827832
ENSE00003492800	43823931	43824005
ENSE00003509296	43829654	43829791
ENSE00003525641	43818046	43818110
ENSE00003528584	43831559	43831677
ENSE00003555647	43811112	43811205
ENSE00003592615	43825756	43825841
ENSE00003600694	43814011	43814091
ENSE00003608430	43831882	43831943
ENSE00003623424	43831244	43831321
ENSE00003652239	43810807	43810915
ENSE00003676214	43814197	43814361
ENSE00003677200	43808956	43809078
ENSE00003680025	43820862	43821058
ENSE00003682902	43830027	43830107
ENSE00003694582	43816038	43816079
ENSE00003903757	43833101	43833146

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 97.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.8005 / max 142.8094, expressed in 1477 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166280	6.0125	1452
196631	1.0505	139
166279	0.7879	420

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.65	gold quality
right atrium auricular region	UBERON:0006631	96.63	gold quality
cerebellar hemisphere	UBERON:0002245	96.61	gold quality
cerebellar cortex	UBERON:0002129	96.51	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.33	gold quality
cardiac atrium	UBERON:0002081	95.04	gold quality
cerebellum	UBERON:0002037	95.03	gold quality
heart left ventricle	UBERON:0002084	94.14	gold quality
cardiac ventricle	UBERON:0002082	93.49	gold quality
heart	UBERON:0000948	91.94	gold quality
upper lobe of left lung	UBERON:0008952	91.36	gold quality
right lung	UBERON:0002167	91.02	gold quality
cortical plate	UBERON:0005343	89.78	gold quality
upper lobe of lung	UBERON:0008948	89.72	gold quality
body of pancreas	UBERON:0001150	88.03	gold quality
thoracic aorta	UBERON:0001515	87.96	gold quality
ascending aorta	UBERON:0001496	87.93	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.64	gold quality
lower esophagus mucosa	UBERON:0035834	87.41	gold quality
omental fat pad	UBERON:0010414	87.38	gold quality
peritoneum	UBERON:0002358	87.35	gold quality
descending thoracic aorta	UBERON:0002345	86.52	gold quality
left uterine tube	UBERON:0001303	86.38	gold quality
pancreatic ductal cell	CL:0002079	86.29	silver quality
ganglionic eminence	UBERON:0004023	86.13	gold quality
right coronary artery	UBERON:0001625	86.12	gold quality
adipose tissue of abdominal region	UBERON:0007808	85.74	gold quality
gall bladder	UBERON:0002110	84.89	gold quality
left coronary artery	UBERON:0001626	84.81	gold quality
mucosa of stomach	UBERON:0001199	84.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.51
E-MTAB-6058	no	99.90

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

55 targeting MPP3, 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-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-6074	98.89	69.64	2187

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 7)

• MPP3, a human homologue of a Drosophila tumor suppressor gene (Discs large), associates with TSCL1, a tumor suppressor gene. (PMID:13679854)
• These data implicate a role for MPP3 in photoreceptor polarity and, by association with MPP5, pinpoint MPP3 as a functional candidate gene for inherited retinopathies. (PMID:16519681)
• TSLC1 strongly inhibits the growth of HepG2 cells in vitro and induces apoptosis. (PMID:17669239)
• Data suggested that epigenetic inactivation of MPP3 frequently occurred during the development of colorectal cancer and might also be a potential biomarker for molecular classification of colorectal cancer patients. (PMID:23011156)
• MPP3 and Dlg, membrane-associated guanylate kinase homologs (MAGuK) proteins, connect CADM1 with p85 of PI3K by forming a multi-protein complex at the periphery of cells. (PMID:24503895)
• MPP3 plays an important role in hepatocellular carcinoma metastasis by promoting cell migration and invasion via up-regulating MMP1 (PMID:24513266)
• a central role of CADM1 in stabilizing the complex with 4.1B and MPP3 (PMID:25780926)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	mpp3a	ENSDARG00000015184
danio_rerio	mpp3b	ENSDARG00000062667
mus_musculus	Mpp3	ENSMUSG00000052373
rattus_norvegicus	Mpp3	ENSRNOG00000033653
drosophila_melanogaster	metro	FBGN0050021
drosophila_melanogaster	vari	FBGN0250785
caenorhabditis_elegans	magu-3	WBGENE00016841
caenorhabditis_elegans		WBGENE00021914

Paralogs (7): PALS1 (ENSG00000072415), MPP4 (ENSG00000082126), PALS2 (ENSG00000105926), MPP2 (ENSG00000108852), MPP1 (ENSG00000130830), CASK (ENSG00000147044), MPP7 (ENSG00000150054)

Protein

Protein identifiers

MAGUK p55 subfamily member 3 — Q13368 (reviewed: Q13368)

Alternative names: Discs large homolog 3, Protein MPP3

All UniProt accessions (3): D3DX46, Q13368, K7EPM7

UniProt curated annotations — full annotation on UniProt →

Function. Participates in cell spreading through the phosphoinositide-3-kinase (PI3K) pathway by connecting CADM1 to DLG1 and the regulatory subunit of phosphoinositide-3-kinase (PI3K). Stabilizes HTR2C at the plasma membrane and prevents its desensitization. May participates in the maintenance of adherens junctions.

Subunit / interactions. Interacts with HTR2C; this interaction stabilizes the receptor at the plasma membrane and prevents the desensitization of the HTR2C receptor-mediated calcium response. Interacts with HTR2A. Interacts with HTR4. Interacts (via PDZ domain) with CADM1 (via C-terminus)Interacts (via PDZ domain) with CADM1; this interaction connects CADM1 with DLG1. Interacts (via Guanylate kinase-like domain) with PALS1. Interacts with DLG1 (via N-terminus); this interaction connects CADM1 with DLG1 and links CADM1 with the regulatory subunit of phosphoinositide-3-kinase (PI3K) by forming a multiprotein complex and participates in cell spreading.

Subcellular location. Cell membrane. Apical cell membrane. Cell junction. Adherens junction.

Tissue specificity. Expressed in retina (at protein level) at the subapical region (SAR) adjacent to adherens junctions at the OLM, and at the OPL.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the MAGUK family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13368-1	1	yes
Q13368-2	2

RefSeq proteins (3): NP_001317162, NP_001340009, NP_001923* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001478	PDZ	Domain
IPR004172	L27_dom	Domain
IPR008144	Guanylate_kin-like_dom	Domain
IPR008145	GK/Ca_channel_bsu	Domain
IPR014775	L27_C	Domain
IPR020590	Guanylate_kinase_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035604	MPP3_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036892	L27_dom_sf	Homologous_superfamily
IPR050716	MAGUK	Family

Pfam: PF00595, PF00625, PF02828, PF07653

UniProt features (10 total): domain 5, chain 1, modified residue 1, splice variant 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13368-F1	78.54	0.40

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 (1): 307

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 465 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, RRAGTTGT_UNKNOWN, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_IONOTROPIC_ACTIVITY_OF_KAINATE_RECEPTORS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, PAX4_01, RORA1_01, NKX25_02, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, KYNG_DNA_DAMAGE_BY_4NQO, BROWNE_HCMV_INFECTION_16HR_UP

GO Biological Process (0):

GO Molecular Function (2): PDZ domain binding (GO:0030165), protein binding (GO:0005515)

GO Cellular Component (6): plasma membrane (GO:0005886), cell-cell junction (GO:0005911), adherens junction (GO:0005912), apical plasma membrane (GO:0016324), membrane (GO:0016020), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein domain specific binding	1
binding	1
membrane	1
cell periphery	1
anchoring junction	1
cell-cell junction	1
apical part of cell	1
plasma membrane region	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

2086 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MPP3	CADM1	Q9BY67	896
MPP3	CADM3	Q8N126	847
MPP3	LIN7A	O14910	789
MPP3	GRIN2A	Q12879	781
MPP3	LIN7C	Q9NUP9	726
MPP3	FBXO45	P0C2W1	719
MPP3	GRIN2B	Q13224	710
MPP3	LCK	P06239	694
MPP3	SLAMF1	Q13291	684
MPP3	LLGL1	Q15334	680
MPP3	MATK	P42679	671
MPP3	KCNA3	P22001	636
MPP3	NECTIN1	Q15223	628
MPP3	NECTIN3	Q9NQS3	625
MPP3	SCRIB	Q14160	620

IntAct

86 interactions, top by confidence:

A	B	Type	Score
MPP3	LIN7C	psi-mi:“MI:0915”(physical association)	0.740
MPP3	LIN7B	psi-mi:“MI:0915”(physical association)	0.670
MPP3	ZNF655	psi-mi:“MI:0915”(physical association)	0.560
LIN7A	MPP3	psi-mi:“MI:0915”(physical association)	0.560
MPP3	BTBD1	psi-mi:“MI:0915”(physical association)	0.560
PKNOX1	MPP3	psi-mi:“MI:0915”(physical association)	0.560
LIN7C	ABLIM1	psi-mi:“MI:0914”(association)	0.530
LIN7B	CASK	psi-mi:“MI:0914”(association)	0.530
MPP3	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MPP3	ABCC4	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF16	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
ASIC3	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
ATP2B4	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
CYSLTR2	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
MPP3	DGKK	psi-mi:“MI:0407”(direct interaction)	0.440
DGKZ	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
FRMPD4	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
FZD7	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
TAMALIN	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
E6	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
ORF putative E6	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA5	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440
KIR3DL3	MPP3	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (44): TRAF2 (Two-hybrid), LIN7A (Two-hybrid), SNTG2 (Two-hybrid), KRTAP10-3 (Two-hybrid), MPP3 (Affinity Capture-MS), MPP3 (Two-hybrid), MPP3 (Affinity Capture-MS), MPP3 (Affinity Capture-RNA), MPP3 (Biochemical Activity), MPP3 (Affinity Capture-Western), MPP3 (Reconstituted Complex), MPP3 (Affinity Capture-MS), MPP3 (Affinity Capture-Western), MPP3 (Affinity Capture-MS), NOA1 (Two-hybrid)

ESM2 similar proteins: A0A0B4J1F4, A0A0G2JXN2, A2AWP8, A2RRH5, C9J798, O43374, O70277, O95294, P04629, P59926, Q0GA42, Q13368, Q14318, Q16512, Q29RM4, Q2HY40, Q2T9P3, Q2TBA3, Q5BIM1, Q5M7W1, Q5R5M3, Q5R811, Q5T7P8, Q5XIS9, Q62746, Q6PFQ7, Q6PFY8, Q7TNM2, Q7TP90, Q7Z4K8, Q8BG60, Q8BHT7, Q8BQC3, Q8C6N3, Q8CIW5, Q8IZ69, Q8NCT1, Q920N2, Q92546, Q925B4

Diamond homologs: A6QQZ7, A8KBF6, A9CB74, B4F7E7, D3ZAA9, E2QY99, G5ECY0, O14936, O34328, O70589, O88910, O88954, P0C0M9, P15454, P31006, P31007, P44310, P46195, P49697, P54936, P65219, P65220, P65221, P70175, P70290, P72648, P93757, P99176, Q00013, Q13368, Q14168, Q15700, Q16774, Q17QN6, Q182S8, Q24210, Q2FHM9, Q2G1U0, Q2QPW1, Q2S8R2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	18
Uncertain significance	243
Likely benign	45
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
11519	NM_021120.4(DLG3):c.1302+1G>A	Pathogenic
127193	NM_021120.4(DLG3):c.357+1G>C	Pathogenic
127194	NM_021120.4(DLG3):c.985+1G>C	Pathogenic
1319664	NM_021120.4(DLG3):c.2266C>T (p.Arg756Ter)	Pathogenic
166996	NM_021120.4(DLG3):c.2280T>G (p.Tyr760Ter)	Pathogenic
1747664	NM_021120.4(DLG3):c.546_549del (p.Val183fs)	Pathogenic
2576624	NM_021120.4(DLG3):c.-8dup	Pathogenic
2577711	NM_021120.4(DLG3):c.100C>T (p.Gln34Ter)	Pathogenic
29942	NM_021120.4(DLG3):c.1092dup (p.Thr365fs)	Pathogenic
29943	NM_021120.4(DLG3):c.1373C>G (p.Ser458Ter)	Pathogenic
3272237	NM_021120.4(DLG3):c.158del (p.Gly53fs)	Pathogenic
3393533	NM_021120.4(DLG3):c.649C>T (p.Arg217Ter)	Pathogenic
3598422	NM_021120.4(DLG3):c.1669C>T (p.Gln557Ter)	Pathogenic
3770157	NM_021120.4(DLG3):c.1349_1350del (p.Ala450fs)	Pathogenic
3899003	NM_021120.4(DLG3):c.791del (p.Gly264fs)	Pathogenic
4734248	NM_021120.4(DLG3):c.1513_1519del (p.Tyr505fs)	Pathogenic
521239	NM_021120.4(DLG3):c.351T>A (p.Tyr117Ter)	Pathogenic
521892	NM_021120.4(DLG3):c.631C>T (p.Arg211Ter)	Pathogenic
58553	GRCh38/hg38 Xp22.33-q28(chrX:26101-155999293)x3	Pathogenic
625217	NM_021120.4(DLG3):c.1375_1378del (p.Val459fs)	Pathogenic
981256	NM_021120.4(DLG3):c.1761dup (p.Glu588Ter)	Pathogenic
987145	NM_021120.4(DLG3):c.1369del (p.Gln457fs)	Pathogenic
1098381	NM_021120.4(DLG3):c.1520+1G>T	Likely pathogenic
11518	NM_021120.4(DLG3):c.985+5G>A	Likely pathogenic
1328590	NM_021120.4(DLG3):c.592C>T (p.Arg198Trp)	Likely pathogenic
1334574	NM_021120.4(DLG3):c.1447C>T (p.Gln483Ter)	Likely pathogenic
2237115	NM_021120.4(DLG3):c.158_159insA (p.Tyr54fs)	Likely pathogenic
2429999	NM_021120.4(DLG3):c.1819+1del	Likely pathogenic
2626899	NM_021120.4(DLG3):c.116dup (p.Tyr39Ter)	Likely pathogenic
3770137	NM_021120.4(DLG3):c.131dup (p.Asn45fs)	Likely pathogenic

SpliceAI

2800 predictions. Top by Δscore:

Variant	Effect	Δscore
17:43808954:A:AC	donor_gain	1.0000
17:43808955:C:CC	donor_gain	1.0000
17:43810805:A:AC	donor_gain	1.0000
17:43810806:C:CC	donor_gain	1.0000
17:43810806:CTT:C	donor_gain	1.0000
17:43811110:A:AC	donor_gain	1.0000
17:43811111:C:CC	donor_gain	1.0000
17:43814009:A:AC	donor_gain	1.0000
17:43814010:C:CC	donor_gain	1.0000
17:43814090:CC:C	acceptor_gain	1.0000
17:43814091:CC:C	acceptor_gain	1.0000
17:43814359:CAGCT:C	acceptor_gain	1.0000
17:43816032:ACTTA:A	donor_loss	1.0000
17:43816035:TA:T	donor_loss	1.0000
17:43816036:A:AC	donor_gain	1.0000
17:43816036:AC:A	donor_gain	1.0000
17:43816037:C:CC	donor_gain	1.0000
17:43816037:C:T	donor_loss	1.0000
17:43816037:CC:C	donor_gain	1.0000
17:43816037:CCCA:C	donor_gain	1.0000
17:43823938:T:A	donor_gain	1.0000
17:43825682:T:TA	donor_gain	1.0000
17:43825731:T:TA	donor_gain	1.0000
17:43825732:C:A	donor_gain	1.0000
17:43825837:CAGGC:C	acceptor_gain	1.0000
17:43825838:AGGCC:A	acceptor_loss	1.0000
17:43825840:GCC:G	acceptor_loss	1.0000
17:43825841:CCTAG:C	acceptor_loss	1.0000
17:43825842:C:CC	acceptor_gain	1.0000
17:43825842:CTAGG:C	acceptor_loss	1.0000

AlphaMissense

3823 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:43820935:A:G	W270R	1.000
17:43820935:A:T	W270R	1.000
17:43827822:A:T	I151N	1.000
17:43811153:A:C	F436L	0.999
17:43811153:A:T	F436L	0.999
17:43811155:A:G	F436L	0.999
17:43820926:C:G	A273P	0.999
17:43820932:A:G	W271R	0.999
17:43820932:A:T	W271R	0.999
17:43820933:C:A	W270C	0.999
17:43820933:C:G	W270C	0.999
17:43823980:A:G	L212P	0.999
17:43825817:A:G	L183P	0.999
17:43825817:A:T	L183H	0.999
17:43825823:T:A	D181V	0.999
17:43825835:A:T	V177D	0.999
17:43827762:G:T	A171E	0.999
17:43827783:C:A	R164M	0.999
17:43827783:C:G	R164T	0.999
17:43827789:A:T	V162E	0.999
17:43827822:A:C	I151S	0.999
17:43827828:G:T	A149D	0.999
17:43827829:C:G	A149P	0.999
17:43827831:C:T	G148D	0.999
17:43827832:C:G	G148R	0.999
17:43829669:C:A	K142N	0.999
17:43829669:C:G	K142N	0.999
17:43829676:A:G	L140S	0.999
17:43829682:A:T	V138D	0.999
17:43829766:A:T	V110D	0.999

dbSNP variants (sampled 300 via entrez): RS1000032890 (17:43824918 G>T), RS1000044590 (17:43818049 G>T), RS1000155053 (17:43833012 G>A), RS1000326283 (17:43804993 G>A), RS1000443985 (17:43805292 A>G), RS1000553829 (17:43829949 G>T), RS1000571563 (17:43829535 G>A,T), RS1000585918 (17:43823362 C>T), RS1000832002 (17:43816794 C>A,T), RS1000903016 (17:43823908 A>C,G), RS1001189228 (17:43832912 G>A,C,T), RS1001239737 (17:43826834 TTTTTTTTTTTC>T), RS1001241298 (17:43832679 G>A,C,T), RS1001257487 (17:43826255 A>C), RS1001389643 (17:43810289 C>T)

Disease associations

OMIM: gene MIM:601114 | disease phenotypes: MIM:300850

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 90	Definitive	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
non-syndromic X-linked intellectual disability	Definitive	XL

Mondo (5): intellectual disability, X-linked 90 (MONDO:0010452), neurodevelopmental disorder (MONDO:0700092), epilepsy (MONDO:0005027), intellectual disability (MONDO:0001071), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (2): X-linked non-syndromic intellectual disability (Orphanet:777), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST002216_17	Triglycerides	1.000000e-08
GCST008070_25	HDL cholesterol levels	2.000000e-10
GCST008070_90	HDL cholesterol levels	9.000000e-09
GCST008074_103	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	8.000000e-20
GCST008074_48	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	5.000000e-21
GCST008075_153	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	9.000000e-34
GCST008075_18	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	7.000000e-31
GCST008083_149	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	7.000000e-21
GCST008083_85	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-22
GCST008084_154	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-41
GCST008084_30	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	3.000000e-36
GCST008085_143	HDL cholesterol levels in current drinkers	4.000000e-12
GCST008085_22	HDL cholesterol levels in current drinkers	2.000000e-13
GCST008087_23	Triglyceride levels in current drinkers	2.000000e-08
GCST008087_97	Triglyceride levels in current drinkers	2.000000e-07
GCST009363_37	Triglyceride levels x short total sleep time interaction (2df test)	4.000000e-09
GCST90002395_640	Mean platelet volume	1.000000e-27

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	3
Cyclosporine	increases expression	2
methyleugenol	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Estradiol	increases expression	1
Hydrogen Peroxide	affects expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Paclitaxel	increases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide