FRMPD4

Summary

FRMPD4 (FERM and PDZ domain containing 4, HGNC:29007) is a protein-coding gene on chromosome Xp22.2, encoding FERM and PDZ domain-containing protein 4 (Q14CM0). Positive regulator of dendritic spine morphogenesis and density.

This gene encodes a multi-domain (WW, PDZ, FERM) containing protein. Through its interaction with other proteins (such as PSD-95), it functions as a positive regulator of dendritic spine morphogenesis and density, and is required for the maintenance of excitatory synaptic transmission.

Source: NCBI Gene 9758 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 578 total — 9 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 31
• MANE Select transcript: NM_001368397

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29007
Approved symbol	FRMPD4
Name	FERM and PDZ domain containing 4
Location	Xp22.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0316
Ensembl gene	ENSG00000169933
Ensembl biotype	protein_coding
OMIM	300838
Entrez	9758

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000380682, ENST00000616992, ENST00000640291, ENST00000656302, ENST00000657176, ENST00000657982, ENST00000672010, ENST00000672340, ENST00000672869, ENST00000673271, ENST00000675598, ENST00000687851

RefSeq mRNA: 9 — MANE Select: NM_001368397 NM_001368395, NM_001368396, NM_001368397, NM_001368398, NM_001368399, NM_001368400, NM_001368401, NM_001368402, NM_014728

CCDS: CCDS35201, CCDS94550, CCDS94551, CCDS94552

Canonical transcript exons

ENST00000675598 — 17 exons

Exon	Start	End
ENSE00001151045	12716069	12717133
ENSE00001151048	12710399	12710537
ENSE00001151059	12706826	12706915
ENSE00001151067	12704359	12704485
ENSE00001151076	12701874	12702010
ENSE00001151084	12694335	12694454
ENSE00001151089	12690195	12690326
ENSE00001151095	12686097	12686204
ENSE00001151101	12683483	12683587
ENSE00001151110	12674863	12674908
ENSE00001207166	12614779	12614881
ENSE00001215426	12609721	12609881
ENSE00001314954	12498680	12498796
ENSE00001485861	12717501	12718790
ENSE00001485864	12707469	12707651
ENSE00003901768	12138473	12139012
ENSE00003904133	12720534	12724523

Expression profiles

Bgee: expression breadth ubiquitous, 117 present calls, max score 95.38.

FANTOM5 (CAGE): breadth broad, TPM avg 1.5984 / max 57.9285, expressed in 386 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195519	0.3393	86
195520	0.3120	164
195522	0.2109	109
195521	0.2023	108
195516	0.1754	62
195517	0.0873	46
195514	0.0818	38
209603	0.0751	37
195518	0.0429	26
195513	0.0275	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	95.38	gold quality
endothelial cell	CL:0000115	92.91	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.62	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.06	gold quality
orbitofrontal cortex	UBERON:0004167	88.78	gold quality
superior frontal gyrus	UBERON:0002661	86.74	gold quality
postcentral gyrus	UBERON:0002581	86.31	gold quality
parietal lobe	UBERON:0001872	85.32	gold quality
primary visual cortex	UBERON:0002436	84.71	gold quality
entorhinal cortex	UBERON:0002728	84.54	gold quality
prefrontal cortex	UBERON:0000451	83.66	gold quality
occipital lobe	UBERON:0002021	83.17	gold quality
CA1 field of hippocampus	UBERON:0003881	82.73	gold quality
lateral nuclear group of thalamus	UBERON:0002736	82.58	gold quality
frontal cortex	UBERON:0001870	81.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.39	gold quality
cortical plate	UBERON:0005343	79.45	gold quality
neocortex	UBERON:0001950	79.44	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	78.72	gold quality
cerebral cortex	UBERON:0000956	78.39	gold quality
Brodmann (1909) area 9	UBERON:0013540	77.84	gold quality
Brodmann (1909) area 10	UBERON:0013541	75.97	gold quality
pons	UBERON:0000988	75.62	gold quality
telencephalon	UBERON:0001893	75.43	gold quality
right frontal lobe	UBERON:0002810	74.84	gold quality
temporal lobe	UBERON:0001871	74.38	gold quality
cerebellar vermis	UBERON:0004720	73.98	silver quality
buccal mucosa cell	CL:0002336	73.90	gold quality
cingulate cortex	UBERON:0003027	73.52	gold quality
anterior cingulate cortex	UBERON:0009835	73.28	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	2933.05
E-HCAD-35	yes	2678.94
E-HCAD-25	yes	1716.30
E-ANND-3	yes	6.52
E-HCAD-30	no	2152.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

232 targeting FRMPD4, 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-190A-3P	100.00	80.35	5520
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038

Literature-anchored findings (GeneRIF, showing 6)

• Preso positively regulates spine density through its interaction with the synaptic plasma membrane, actin filaments, PSD-95, and the betaPix-based Rac1 signaling pathway. (PMID:19118189)
• A crystal structure of Frmpd4-bound LGN in an oxidized form is also reported, although oxidation does not appear to strongly affect the interaction with Frmpd4. (PMID:25664792)
• Study suggests that the variant rs5979717 in FRMPD4 may play a role in schizophrenia etiology in females (PMID:26555035)
• The findings point to an important role of FRMPD4 in normal cognitive development and function in humans and mice, and support the hypothesis that FRMPD4 mutations cause ID by disrupting dendritic spine morphogenesis in glutamatergic neurons. (PMID:29267967)
• Structure of the FERM domain of a neural scaffold protein FRMPD4 implicated in X-linked intellectual disability. (PMID:33216857)
• Investigation of FRMPD4 variants associated with X-linked epilepsy. (PMID:37330374)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	frmpd4	ENSDARG00000075685
mus_musculus	Frmpd4	ENSMUSG00000049176
rattus_norvegicus	Frmpd4	ENSRNOG00000004118
drosophila_melanogaster	CG42788	FBGN0261859
caenorhabditis_elegans		WBGENE00001494

Paralogs (2): FRMPD1 (ENSG00000070601), FRMPD3 (ENSG00000147234)

Protein

Protein identifiers

FERM and PDZ domain-containing protein 4 — Q14CM0 (reviewed: Q14CM0)

Alternative names: PDZ domain-containing protein 10, PSD-95-interacting regulator of spine morphogenesis

All UniProt accessions (8): Q14CM0, A0A087WYX8, A0A1W2PQW0, A0A590UJI1, A0A590UJL7, A0A5F9ZH12, A0A5F9ZHT2, A0A6Q8PH73

UniProt curated annotations — full annotation on UniProt →

Function. Positive regulator of dendritic spine morphogenesis and density. Required for the maintenance of excitatory synaptic transmission. Binds phosphatidylinositol 4,5-bisphosphate.

Subunit / interactions. Interacts (via C-terminus) with DLG1, DLG2, DLG3 and DLG4/PSD95. Interacts (via N-terminus) with ARHGEF7; the interaction is mediated by the PDZ domain. Interacts with GPSM2 (via TPR repeat region).

Subcellular location. Cell projection. Dendritic spine.

Disease relevance. Intellectual developmental disorder, X-linked 104 (XLID104) [MIM:300983] A form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked forms, while syndromic forms present with associated physical, neurological and/or psychiatric manifestations. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The FERM domain mediates the interaction with phosphatidylinositol 4,5-bisphosphate.

RefSeq proteins (9): NP_001355324, NP_001355325, NP_001355326, NP_001355327, NP_001355328, NP_001355329, NP_001355330, NP_001355331, NP_055543 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000299	FERM_domain	Domain
IPR001202	WW_dom	Domain
IPR001478	PDZ	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR014352	FERM/acyl-CoA-bd_prot_sf	Homologous_superfamily
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR035963	FERM_2	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR041779	FRMPD1/3/4_FERM_C	Domain
IPR049385	FAK1-like_FERM_C	Domain

Pfam: PF00373, PF00595, PF21477

UniProt features (54 total): helix 15, strand 14, region of interest 7, mutagenesis site 5, compositionally biased region 4, domain 3, turn 3, chain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4WND	X-RAY DIFFRACTION	1.5
4WNE	X-RAY DIFFRACTION	2
4WNG	X-RAY DIFFRACTION	2.11
7BYJ	X-RAY DIFFRACTION	2.49
4WNF	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14CM0-F1	54.86	0.22

Functional residue map

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

Mutagenesis-validated functional residues (5):

Position	Phenotype
102	abolishes the interaction with arhgef7. mutant overexpression in cultured neurons does not induce a significant increase
990	nearly abolishes interaction with gpsm2; when associated with 1010-a-a-1011.
1010–1011	nearly abolishes interaction with gpsm2; when associated with a-990.
1319–1322	abolishes the interaction with dlg1, dlg2, dlg3 and dlg4/psd95. reduces protein localization to dendritic spines.
1320	abolishes the interaction with dlg4/psd95. reduces protein localization to dendritic spines.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 169 (showing top): BENPORATH_ES_WITH_H3K27ME3, AAGCCAT_MIR135A_MIR135B, TATTATA_MIR374, SHIPP_DLBCL_CURED_VS_FATAL_DN, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPSE_STRUCTURE_OR_ACTIVITY, TTGGAGA_MIR5155P_MIR519E, GOCC_NEURON_PROJECTION, CTCAAGA_MIR526B, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_DN, GOCC_POSTSYNAPSE, GOCC_NEURON_SPINE, GOCC_SYNAPSE, GOCC_SOMATODENDRITIC_COMPARTMENT

GO Biological Process (2): positive regulation of synapse structural plasticity (GO:0051835), postsynaptic actin cytoskeleton organization (GO:0098974)

GO Molecular Function (3): phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (8): protein-containing complex (GO:0032991), dendritic spine (GO:0043197), cytoskeleton (GO:0005856), postsynaptic density (GO:0014069), cell projection (GO:0042995), synapse (GO:0045202), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
synapse	2
positive regulation of cellular component organization	1
regulation of synapse structural plasticity	1
actin cytoskeleton organization	1
postsynaptic cytoskeleton organization	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
cellular_component	1
dendrite	1
neuron spine	1
postsynapse	1
intracellular membraneless organelle	1
asymmetric synapse	1
postsynaptic specialization	1
cell junction	1

Protein interactions and networks

STRING

1598 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FRMPD4	DLG4	P78352	587
FRMPD4	MPP3	Q13368	518
FRMPD4	ARHGEF7	Q14155	505
FRMPD4	DLG3	Q92796	497
FRMPD4	PDZD2	O15018	492
FRMPD4	SNX27	Q96L92	475
FRMPD4	ARSF	P54793	447
FRMPD4	GSTA3	Q16772	441
FRMPD4	PALS1	Q8N3R9	439
FRMPD4	GSTA2	P09210	425
FRMPD4	GSTA1	P08263	412
FRMPD4	BCL11A	Q9H165	404
FRMPD4	CNKSR2	Q8WXI2	392
FRMPD4	HBS1L	Q9Y450	389
FRMPD4	HBB	P02023	375

IntAct

612 interactions, top by confidence:

A	B	Type	Score
FRMPD4	DLG1	psi-mi:“MI:0915”(physical association)	0.720
SCRIB	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.720
DLG1	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.720
DLG4	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.720
DLG4	FRMPD4	psi-mi:“MI:0915”(physical association)	0.720
FRMPD4	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.720
FRMPD4	SCRIB	psi-mi:“MI:0915”(physical association)	0.720
FRMPD4	DLG1	psi-mi:“MI:0407”(direct interaction)	0.720
FRMPD4	DLG4	psi-mi:“MI:0407”(direct interaction)	0.720
DLG3	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.620
SNTB1	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.620
SNTA1	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.620
FRMPD4	DLG3	psi-mi:“MI:0407”(direct interaction)	0.620
FRMPD4	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.620
E	FRMPD4	psi-mi:“MI:0915”(physical association)	0.610

BioGRID (12): FRMPD4 (Affinity Capture-MS), FRMPD4 (Proximity Label-MS), FRMPD4 (Affinity Capture-Western), FRMPD4 (Protein-peptide), FRMPD4 (Protein-peptide), FRMPD4 (Affinity Capture-MS), FRMPD4 (Affinity Capture-MS), HSP90AA1 (Cross-Linking-MS (XL-MS)), FRMPD4 (Reconstituted Complex), FRMPD4 (Proximity Label-MS), FRMPD4 (Two-hybrid), FRMPD4 (Two-hybrid)

ESM2 similar proteins: A0JNA8, A2AFR3, A2AWP8, F1LXF1, O15034, O94844, O94967, O95267, P11274, P28028, Q01826, Q08BT5, Q14161, Q14CM0, Q15139, Q3UGM2, Q3UHE1, Q4R4I0, Q5R5M3, Q5VUG0, Q5XIS9, Q60611, Q62101, Q66H91, Q68FF6, Q6NZQ4, Q6PAJ1, Q6PB44, Q6ZW49, Q6ZWH5, Q80U28, Q8BWW9, Q8BZ03, Q8CGF6, Q8TCU6, Q8VDD9, Q8VI24, Q96GD3, Q9BZ71, Q9BZL6

Diamond homologs: A2AFR3, A2AKB4, E2QYC9, F1MAD2, O62683, O95049, Q14CM0, Q5JV73, Q5SYB0, Q63ZW7, Q8NI35, Q9QXY1, A0A8C0TYJ0, A7UA95, A8KBF6, O14910, O35274, O35867, O35889, O54824, O55164, O75970, O88951, O88952, P31016, P51140, P55196, P57105, P70175, P78352, Q0P5E6, Q0P5F3, Q12959, Q13424, Q13425, Q13884, Q28626, Q28C55, Q2KIB6, Q32LM6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 152 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
Ras activation upon Ca2+ influx through NMDA receptor	6	30.6×	4e-06
Long-term potentiation	7	29.7×	5e-07
Unblocking of NMDA receptors, glutamate binding and activation	6	29.1×	4e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	6	29.1×	4e-06
Synaptic adhesion-like molecules	5	24.3×	1e-04
Assembly and cell surface presentation of NMDA receptors	9	20.4×	1e-07
Neurexins and neuroligins	11	19.3×	5e-09
EPHB-mediated forward signaling	5	11.9×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	7	28.6×	4e-06
receptor clustering	6	26.4×	5e-05
positive regulation of excitatory postsynaptic potential	5	18.5×	1e-03
regulation of postsynaptic membrane neurotransmitter receptor levels	5	17.4×	1e-03
Rho protein signal transduction	6	10.5×	2e-03
protein-containing complex assembly	9	7.2×	1e-03
chemical synaptic transmission	12	6.5×	1e-04
cell-cell adhesion	9	6.4×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	15
Uncertain significance	341
Likely benign	92
Benign	21

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
2499920	NM_001368397.1(FRMPD4):c.2776del (p.Gln926fs)	Pathogenic
254682	NM_001368397.1(FRMPD4):c.1851del (p.Cys618fs)	Pathogenic
2580164	NM_001368397.1(FRMPD4):c.1411G>T (p.Glu471Ter)	Pathogenic
2840087	NM_001368397.1(FRMPD4):c.3145C>T (p.Gln1049Ter)	Pathogenic
3895974	NC_000023.10:g.(12157132_12516798)_(12704324_12708313)del	Pathogenic
564692	GRCh37/hg19 Xp22.33-22.2(chrX:168546-16404364)x1	Pathogenic
599279	NC_000023.10:g.12515801_12581900del	Pathogenic
599280	NM_001368397.1(FRMPD4):c.856C>T (p.Arg286Ter)	Pathogenic
872685	NM_001368397.1(FRMPD4):c.933+1G>A	Pathogenic
1320187	NM_001368397.1(FRMPD4):c.1151C>A (p.Ser384Ter)	Likely pathogenic
1700089	NM_001368397.1(FRMPD4):c.3025_3028del (p.Asp1009fs)	Likely pathogenic
1701591	NM_001368397.1(FRMPD4):c.561_573+2delinsA	Likely pathogenic
1709267	NM_001368397.1(FRMPD4):c.561del (p.Asn187fs)	Likely pathogenic
2444249	NM_001368397.1(FRMPD4):c.3258del (p.Arg1087fs)	Likely pathogenic
2505507	NM_001368397.1(FRMPD4):c.3024dup (p.Asp1009Ter)	Likely pathogenic
254683	NM_001368397.1(FRMPD4):c.1657T>C (p.Cys553Arg)	Likely pathogenic
2576097	NM_001368397.1(FRMPD4):c.3108del (p.Lys1037fs)	Likely pathogenic
3062128	NM_001368397.1(FRMPD4):c.1071-1G>A	Likely pathogenic
3235747	NM_001368397.1(FRMPD4):c.2800del (p.Arg934fs)	Likely pathogenic
3236780	NM_001368397.1(FRMPD4):c.1335T>A (p.Tyr445Ter)	Likely pathogenic
3338501	NM_001368397.1(FRMPD4):c.1927C>T (p.Gln643Ter)	Likely pathogenic
3777257	NM_001368397.1(FRMPD4):c.3144dup (p.Gln1049fs)	Likely pathogenic
487572	NC_000023.10:g.11600773_12249902del649130	Likely pathogenic
976150	NM_001368397.1(FRMPD4):c.1298del (p.Lys433fs)	Likely pathogenic

SpliceAI

1666 predictions. Top by Δscore:

Variant	Effect	Δscore
X:12177769:A:G	donor_gain	1.0000
X:12205948:G:GT	donor_gain	1.0000
X:12154407:T:A	acceptor_gain	0.9900
X:12218126:T:G	acceptor_gain	0.9900
X:12306409:A:T	donor_gain	0.9900
X:12306426:A:G	donor_gain	0.9900
X:12306456:AACC:A	donor_gain	0.9900
X:12306457:ACCA:A	donor_gain	0.9900
X:12139008:TCGAG:T	donor_loss	0.9800
X:12139009:CGAG:C	donor_loss	0.9800
X:12139010:GAGG:G	donor_loss	0.9800
X:12139011:AGGTA:A	donor_loss	0.9800
X:12139012:GGT:G	donor_loss	0.9800
X:12139013:G:A	donor_loss	0.9800
X:12139014:T:G	donor_loss	0.9800
X:12265083:GCCT:G	acceptor_gain	0.9800
X:12277803:A:AG	acceptor_gain	0.9800
X:12299375:A:AG	donor_gain	0.9800
X:12306453:T:G	donor_gain	0.9800
X:12306464:A:AG	donor_gain	0.9700
X:12306898:A:G	donor_gain	0.9700
X:12177750:ATAGC:A	donor_gain	0.9600
X:12306458:C:G	donor_gain	0.9600
X:12138975:G:GT	donor_gain	0.9400
X:12138986:C:G	donor_gain	0.9400
X:12170328:AGAC:A	donor_gain	0.9400
X:12142443:C:A	donor_gain	0.9300
X:12203593:A:AG	donor_gain	0.9300
X:12239402:GTTT:G	donor_gain	0.9300
X:12306420:GA:G	donor_gain	0.9300

AlphaMissense

11540 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:12609824:G:A	G88R	1.000
X:12609824:G:C	G88R	1.000
X:12609825:G:A	G88E	1.000
X:12609827:T:C	F89L	1.000
X:12609828:T:C	F89S	1.000
X:12609829:T:A	F89L	1.000
X:12609829:T:G	F89L	1.000
X:12609830:G:C	G90R	1.000
X:12609831:G:A	G90D	1.000
X:12609833:T:C	F91L	1.000
X:12609834:T:C	F91S	1.000
X:12609835:T:A	F91L	1.000
X:12609835:T:G	F91L	1.000
X:12609864:T:A	V101D	1.000
X:12614818:T:G	I120S	1.000
X:12614866:T:A	V136D	1.000
X:12614875:T:C	L139P	1.000
X:12614878:T:A	V140D	1.000
X:12674880:T:A	I147K	1.000
X:12674886:T:C	L149P	1.000
X:12674892:T:A	V151D	1.000
X:12683526:T:C	L171S	1.000
X:12683552:T:C	F180L	1.000
X:12683553:T:C	F180S	1.000
X:12683554:C:A	F180L	1.000
X:12683554:C:G	F180L	1.000
X:12686137:T:A	V205D	1.000
X:12686140:T:C	L206S	1.000
X:12686146:T:A	V208D	1.000
X:12686152:T:C	L210P	1.000

dbSNP variants (sampled 300 via entrez): RS1000000085 (X:12384530 A>T), RS1000003833 (X:11920492 T>C), RS1000012118 (X:12429193 T>A,C), RS1000018868 (X:12176327 C>T), RS1000019843 (X:12108700 A>T), RS1000028452 (X:12511449 T>G), RS1000031239 (X:12415933 T>G), RS1000033183 (X:12170982 G>A,T), RS1000035198 (X:12491802 G>C), RS1000037705 (X:11985346 G>C,T), RS1000047642 (X:12631678 G>A), RS1000052580 (X:11860949 T>C,G), RS1000055374 (X:11890972 C>T), RS1000065014 (X:12441746 C>T), RS1000069874 (X:12092263 T>C)

Disease associations

OMIM: gene MIM:300838 | disease phenotypes: MIM:300983, MIM:300830

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 104	Strong	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
X-linked complex neurodevelopmental disorder	Definitive	XL

Mondo (6): intellectual disability, X-linked 104 (MONDO:0010509), autism, susceptibility to, X-linked 4 (MONDO:0010440), neurodevelopmental disorder (MONDO:0700092), X-linked complex neurodevelopmental disorder (MONDO:0100148), intellectual disability (MONDO:0001071), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000218	High palate
HP:0000243	Trigonocephaly
HP:0000278	Retrognathia
HP:0000348	High forehead
HP:0000377	Abnormal pinna morphology
HP:0000431	Wide nasal bridge
HP:0000456	Bifid nasal tip
HP:0000486	Strabismus
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000817	Reduced eye contact
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001419	X-linked recessive inheritance
HP:0002079	Hypoplasia of the corpus callosum
HP:0002120	Cerebral cortical atrophy
HP:0002188	Delayed CNS myelination
HP:0002194	Delayed gross motor development
HP:0002236	Frontal upsweep of hair
HP:0003593	Infantile onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST011377_7	Shoulder impingement or rotator cuff tear	2.000000e-09

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
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

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression, increases expression	4
bisphenol S	decreases expression, decreases methylation	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation, increases mutagenesis	2
bisphenol F	affects cotreatment, decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
kojic acid	decreases expression	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Troglitazone	decreases expression	1
Arbutin	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Smoke	increases expression	1
Triclosan	decreases expression	1
Valproic Acid	decreases methylation	1
1-Methyl-3-isobutylxanthine	decreases expression, affects cotreatment	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

299 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,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays