MED27

Summary

MED27 (mediator complex subunit 27, HGNC:2377) is a protein-coding gene on chromosome 9q34.13, encoding Mediator of RNA polymerase II transcription subunit 27 (Q6P2C8). Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. It is a common-essential gene (DepMap: required in 96.5% of cancer cell lines).

The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 5.

Source: NCBI Gene 9442 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 61 total — 7 pathogenic
• Phenotypes (HPO): 33
• Cancer dependency (DepMap): dependent in 96.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_004269

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2377
Approved symbol	MED27
Name	mediator complex subunit 27
Location	9q34.13
Locus type	gene with protein product
Status	Approved
Aliases	TRAP37, CRSP34, MED3
Ensembl gene	ENSG00000160563
Ensembl biotype	protein_coding
OMIM	605044
Entrez	9442

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000292035, ENST00000357028, ENST00000444872, ENST00000474263, ENST00000650776, ENST00000651555, ENST00000651950, ENST00000897371, ENST00000897372, ENST00000897373, ENST00000897374, ENST00000897375, ENST00000951019

RefSeq mRNA: 3 — MANE Select: NM_004269 NM_001253881, NM_001253882, NM_004269

CCDS: CCDS59153, CCDS6945, CCDS69689

Canonical transcript exons

ENST00000292035 — 8 exons

Exon	Start	End
ENSE00001095399	131893885	131893992
ENSE00001095406	131884058	131884099
ENSE00001193043	131939381	131939474
ENSE00001193047	132014337	132014467
ENSE00001305857	131863063	131863140
ENSE00001880013	132079642	132079867
ENSE00003708393	132077442	132077586
ENSE00003841748	131860112	131860672

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 96.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.1223 / max 39.9712, expressed in 1706 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102879	5.1223	1706

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	96.39	gold quality
endothelial cell	CL:0000115	95.02	gold quality
secondary oocyte	CL:0000655	92.84	gold quality
ganglionic eminence	UBERON:0004023	92.07	gold quality
islet of Langerhans	UBERON:0000006	91.38	gold quality
popliteal artery	UBERON:0002250	90.51	gold quality
tibial artery	UBERON:0007610	90.50	gold quality
aorta	UBERON:0000947	90.17	gold quality
ascending aorta	UBERON:0001496	89.93	gold quality
thoracic aorta	UBERON:0001515	89.93	gold quality
ventricular zone	UBERON:0003053	89.84	gold quality
descending thoracic aorta	UBERON:0002345	89.30	gold quality
hair follicle	UBERON:0002073	88.87	gold quality
left coronary artery	UBERON:0001626	88.56	gold quality
gingival epithelium	UBERON:0001949	88.50	gold quality
right coronary artery	UBERON:0001625	88.34	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.18	gold quality
stromal cell of endometrium	CL:0002255	88.12	gold quality
prefrontal cortex	UBERON:0000451	88.07	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.90	gold quality
coronary artery	UBERON:0001621	87.80	gold quality
middle temporal gyrus	UBERON:0002771	87.38	gold quality
gastrocnemius	UBERON:0001388	87.16	gold quality
apex of heart	UBERON:0002098	87.14	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.03	gold quality
cortical plate	UBERON:0005343	87.00	gold quality
skin of leg	UBERON:0001511	86.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.78	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.69	gold quality
lower esophagus	UBERON:0013473	86.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting MED27, 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-340-5P	100.00	72.50	4437
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-5681A	97.99	67.17	1658
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-612	97.26	65.95	1597
HSA-MIR-6860	97.21	66.31	1656

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 9)

• MED27 promotes melanoma growth by targeting AKT/MAPK and NF-kappaB/iNOS signaling pathways. (PMID:26797421)
• The findings of the present study may aid in the clarification of the function of miR18a, particularly as regards its role in the regulation of Osteosarcoma (OS)cell apoptosis, and indicate that MED27 may be a potential novel therapeutic target in the treatment of OS. (PMID:29693135)
• The MED27 plays a negative role in adrenal cortical carcinoma (ACC) occurrence and progression and could be utilized as a new therapeutic target in ACC prevention and treatment. (PMID:29730647)
• MED27 promotes malignant behavior of cells by affecting Sp1 in breast cancer. (PMID:32633372)
• CRSP8 promotes thyroid cancer progression by antagonizing IKKalpha-induced cell differentiation. (PMID:33162555)
• MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia. (PMID:33443317)
• Knockdown of mediator complex subunit 27 suppresses gastric cancer cell metastasis and angiogenesis via Wnt/beta-catenin pathway. (PMID:36371844)
• MED27 plays a tumor-promoting role in breast cancer progression by targeting KLF4. (PMID:36786527)
• Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders. (PMID:37517035)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	med27	ENSDARG00000009681
mus_musculus	Med27	ENSMUSG00000026799
rattus_norvegicus	Med27	ENSRNOG00000013933
drosophila_melanogaster	MED27	FBGN0037359

Protein

Protein identifiers

Mediator of RNA polymerase II transcription subunit 27 — Q6P2C8 (reviewed: Q6P2C8)

Alternative names: Cofactor required for Sp1 transcriptional activation subunit 8, Mediator complex subunit 27, P37 TRAP/SMCC/PC2 subunit, Transcriptional coactivator CRSP34

All UniProt accessions (3): Q6P2C8, A0A494C0K7, A0A494C0P0

UniProt curated annotations — full annotation on UniProt →

Function. Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.

Subunit / interactions. Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.

Subcellular location. Nucleus.

Disease relevance. Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia (NEDSCAC) [MIM:619286] An autosomal recessive disorder characterized by global developmental delay, impaired intellectual development, and poor or absent speech. More severely affected individuals do not achieve independent ambulation, whereas others develop some speech and can walk, or show regression later in childhood. Additional features include axial hypotonia, peripheral spasticity, dystonia, cataracts, and seizures. Brain imaging usually shows cerebellar hypoplasia, thin corpus callosum, cerebral atrophy, and hypomyelination. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Mediator complex subunit 27 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6P2C8-1	1	yes
Q6P2C8-2	2
Q6P2C8-4	3

RefSeq proteins (3): NP_001240810, NP_001240811, NP_004260* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR021627	Mediator_Med27	Family

Pfam: PF11571

UniProt features (35 total): helix 8, sequence variant 7, sequence conflict 6, strand 5, turn 3, splice variant 3, modified residue 2, chain 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
7EMF	ELECTRON MICROSCOPY	3.5
8TRH	ELECTRON MICROSCOPY	3.7
7ENA	ELECTRON MICROSCOPY	4.07
7ENC	ELECTRON MICROSCOPY	4.13
8GXS	ELECTRON MICROSCOPY	4.16
7ENJ	ELECTRON MICROSCOPY	4.4
7NVR	ELECTRON MICROSCOPY	4.5
8T9D	ELECTRON MICROSCOPY	4.66
7LBM	ELECTRON MICROSCOPY	4.8
8GXQ	ELECTRON MICROSCOPY	5.04
8TQW	ELECTRON MICROSCOPY	8.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6P2C8-F1	82.94	0.56

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 (2): 132, 134

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-212436	Generic Transcription Pathway
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-9833110	RSV-host interactions
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-556833	Metabolism of lipids
R-HSA-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9818564	Epigenetic regulation of gene expression by MLL3 and MLL4 complexes
R-HSA-9820952	Respiratory Syncytial Virus Infection Pathway
R-HSA-9824446	Viral Infection Pathways
R-HSA-9843745	Adipogenesis
R-HSA-9851695	Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes
R-HSA-9917777	Epigenetic regulation by WDR5-containing histone modifying complexes

MSigDB gene sets: 177 (showing top): REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_MAINTENANCE_OF_CELL_NUMBER, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_TRANSCRIPTION_INITIATION_AT_RNA_POLYMERASE_II_PROMOTER, WEST_ADRENOCORTICAL_CARCINOMA_VS_ADENOMA_UP, KIM_RESPONSE_TO_TSA_AND_DECITABINE_DN, GOBP_PROTEIN_DNA_COMPLEX_ORGANIZATION, TAL1BETAE47_01, GOBP_POSITIVE_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_ELONGATION, GOBP_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_ELONGATION, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_UP, GOCC_RNA_POLYMERASE_II_TRANSCRIPTION_REGULATOR_COMPLEX, GOCC_TRANSCRIPTION_REGULATOR_COMPLEX

GO Biological Process (7): regulation of transcription by RNA polymerase II (GO:0006357), transcription initiation at RNA polymerase II promoter (GO:0006367), protein ubiquitination (GO:0016567), positive regulation of transcription elongation by RNA polymerase II (GO:0032968), somatic stem cell population maintenance (GO:0035019), RNA polymerase II preinitiation complex assembly (GO:0051123), positive regulation of transcription initiation by RNA polymerase II (GO:0060261)

GO Molecular Function (3): transcription coactivator activity (GO:0003713), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515)

GO Cellular Component (8): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), nucleolus (GO:0005730), cytosol (GO:0005829), mediator complex (GO:0016592), core mediator complex (GO:0070847)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Gene expression (Transcription)	2
Regulation of lipid metabolism by PPARalpha	1
RNA Polymerase II Transcription	1
Adipogenesis	1
Respiratory Syncytial Virus Infection Pathway	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Metabolism of lipids	1
Metabolism	1
Disease	1
Epigenetic regulation by WDR5-containing histone modifying complexes	1
Viral Infection Pathways	1
Infectious disease	1
Developmental Biology	1
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	2
positive regulation of transcription by RNA polymerase II	2
transcription initiation at RNA polymerase II promoter	2
nuclear lumen	2
cellular anatomical structure	2
regulation of DNA-templated transcription	1
DNA-templated transcription initiation	1
protein modification by small protein conjugation	1
transcription elongation by RNA polymerase II	1
positive regulation of DNA-templated transcription, elongation	1
regulation of transcription elongation by RNA polymerase II	1
stem cell population maintenance	1
transcription preinitiation complex assembly	1
regulation of transcription initiation by RNA polymerase II	1
positive regulation of DNA-templated transcription initiation	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
intracellular protein-containing complex	1
transferase complex	1
intracellular membrane-bounded organelle	1
protein-containing complex	1
intracellular membraneless organelle	1
cytoplasm	1
core mediator complex	1
nuclear protein-containing complex	1
RNA polymerase II transcription regulator complex	1

Protein interactions and networks

STRING

2002 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MED27	MED29	Q9NX70	994
MED27	MED17	Q9NVC6	977
MED27	MED30	Q96HR3	969
MED27	MED7	O43513	963
MED27	MED15	Q96RN5	962
MED27	MED11	Q9P086	953
MED27	MED19	A0JLT2	949
MED27	MED22	Q15528	946
MED27	MED31	Q9Y3C7	925
MED27	MED16	Q9Y2X0	908
MED27	MED10	Q9BTT4	900
MED27	MED14	O60244	891
MED27	MED24	O75448	872
MED27	MED20	Q9H944	849
MED27	MED18	Q9BUE0	835

IntAct

135 interactions, top by confidence:

A	B	Type	Score
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
MED10	MED19	psi-mi:“MI:0915”(physical association)	0.910
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
MED21	MED19	psi-mi:“MI:0914”(association)	0.880
MED17	MED22	psi-mi:“MI:0914”(association)	0.860
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
CDK8	MED19	psi-mi:“MI:0914”(association)	0.850
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
MED18	MED19	psi-mi:“MI:0914”(association)	0.840
MED31	MED19	psi-mi:“MI:0914”(association)	0.840
MED7	MED19	psi-mi:“MI:0914”(association)	0.840
MED11	MED19	psi-mi:“MI:0914”(association)	0.840

BioGRID (253): MED27 (Reconstituted Complex), MED27 (Affinity Capture-MS), MED27 (Affinity Capture-MS), MED27 (Affinity Capture-MS), MED27 (Affinity Capture-MS), MED27 (Affinity Capture-MS), MED12 (Co-fractionation), MED16 (Co-fractionation), MED17 (Co-fractionation), MED27 (Co-fractionation), MED27 (Co-fractionation), MED27 (Co-fractionation), MED27 (Co-fractionation), MED27 (Co-fractionation), MED27 (Co-fractionation)

ESM2 similar proteins: A4IH75, B0S6R1, F4K265, O14417, O75165, O94915, P28660, P60670, P97878, Q10LJ0, Q2HJE0, Q2TBN7, Q3B736, Q3B8G8, Q3TPX4, Q499N2, Q4R6Q7, Q4R708, Q556Y9, Q5E9X5, Q5R6U8, Q5R8B7, Q5RBT3, Q5VZE5, Q5XHA1, Q5ZHV2, Q642Q3, Q6AY69, Q6DE58, Q6DKG0, Q6GLR7, Q6NPF4, Q6P2C8, Q6PFL0, Q6PHQ8, Q6Q7J5, Q7T322, Q8BJ63, Q8TAT6, Q8VDP2

Diamond homologs: Q171Y8, Q2TBN7, Q3B8G8, Q5R6U8, Q5XHA1, Q642Q3, Q6P2C8, Q6PFL0, Q6Q7J5, Q7QCJ9, Q9DB40, Q9VNG0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MED27	“form complex”	“Core mediator complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 71 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
Respiratory Syncytial Virus Infection Pathway	27	104.2×	6e-49
RSV-host interactions	27	82.8×	5e-46
Adipogenesis	27	82.8×	5e-46
Regulation of lipid metabolism by PPARalpha	27	74.6×	1e-44
FGFR2 mutant receptor activation	5	74.6×	2e-08
Signaling by FGFR2 IIIa TM	6	70.7×	1e-09
Transcriptional regulation of white adipocyte differentiation	27	68.7×	1e-43
Abortive elongation of HIV-1 transcript in the absence of Tat	7	68.2×	7e-11

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	23	117.3×	7e-42
RNA polymerase II preinitiation complex assembly	24	110.6×	7e-43
positive regulation of transcription initiation by RNA polymerase II	24	110.6×	7e-43
somatic stem cell population maintenance	11	46.2×	4e-14
transcription initiation at RNA polymerase II promoter	7	44.4×	1e-08
transcription by RNA polymerase II	11	13.2×	3e-08
protein ubiquitination	11	7.7×	4e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	0
Uncertain significance	34
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1064746	NM_004269.4(MED27):c.776C>T (p.Pro259Leu)	Pathogenic
1064748	NM_004269.4(MED27):c.392_393del (p.Gln131fs)	Pathogenic
1064751	NM_004269.4(MED27):c.682-2A>G	Pathogenic
3063071	GRCh37/hg19 9p24.3-q34.3(chr9:203861-141020389)x3	Pathogenic
4686653	H179P	Pathogenic
4686654	MED27, VAL242ALA (rs1589166413)	Pathogenic
4686655	MED27, TYR273CYS	Pathogenic

SpliceAI

2684 predictions. Top by Δscore:

Variant	Effect	Δscore
9:131863060:TA:T	donor_loss	1.0000
9:131863061:A:AC	donor_gain	1.0000
9:131863061:ACCAT:A	donor_loss	1.0000
9:131863062:C:CA	donor_loss	1.0000
9:131863062:C:CC	donor_gain	1.0000
9:131863140:CCTG:C	acceptor_loss	1.0000
9:131863141:C:CC	acceptor_gain	1.0000
9:131863142:T:G	acceptor_loss	1.0000
9:131893879:GCTTA:G	donor_loss	1.0000
9:131893880:CTTA:C	donor_loss	1.0000
9:131893881:TTA:T	donor_loss	1.0000
9:131893882:TACC:T	donor_loss	1.0000
9:131893883:A:C	donor_loss	1.0000
9:131939374:ATCTT:A	donor_loss	1.0000
9:131939375:TCTTA:T	donor_loss	1.0000
9:131939376:CTTA:C	donor_loss	1.0000
9:131939377:TTA:T	donor_loss	1.0000
9:131939378:TA:T	donor_loss	1.0000
9:131939379:A:AC	donor_gain	1.0000
9:131939379:A:C	donor_loss	1.0000
9:131939380:C:CC	donor_gain	1.0000
9:131939380:C:G	donor_loss	1.0000
9:131939470:CATAT:C	acceptor_gain	1.0000
9:131939472:TAT:T	acceptor_gain	1.0000
9:131939472:TATC:T	acceptor_loss	1.0000
9:131939473:AT:A	acceptor_gain	1.0000
9:131939474:TCTA:T	acceptor_loss	1.0000
9:131939475:C:CC	acceptor_gain	1.0000
9:131939476:T:A	acceptor_loss	1.0000
9:132014335:A:AC	donor_gain	1.0000

AlphaMissense

2043 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:131860547:G:C	C309W	1.000
9:131860549:A:G	C309R	1.000
9:131860583:C:A	R297S	1.000
9:131860583:C:G	R297S	1.000
9:131860584:C:A	R297M	1.000
9:131860584:C:G	R297T	1.000
9:131860588:A:G	W296R	1.000
9:131860588:A:T	W296R	1.000
9:131860631:G:C	C281W	1.000
9:131860632:C:T	C281Y	1.000
9:131860633:A:G	C281R	1.000
9:131860667:C:A	W269C	1.000
9:131860667:C:G	W269C	1.000
9:131860669:A:G	W269R	1.000
9:131860669:A:T	W269R	1.000
9:131863076:A:T	V263D	1.000
9:131863110:G:C	H252D	1.000
9:131863112:A:G	L251P	1.000
9:131863118:G:T	A249D	1.000
9:131863127:G:T	A246D	1.000
9:131863128:C:G	A246P	1.000
9:131939385:A:G	L190P	1.000
9:132014413:G:T	R135S	1.000
9:132077451:C:A	W113C	1.000
9:132077451:C:G	W113C	1.000
9:132077453:A:G	W113R	1.000
9:132077453:A:T	W113R	1.000
9:132077470:A:G	L107P	1.000
9:132077511:G:C	S93R	1.000
9:132077511:G:T	S93R	1.000

dbSNP variants (sampled 300 via entrez): RS1000006118 (9:132062830 C>T), RS1000006636 (9:131950942 T>A), RS1000006680 (9:132040489 C>T), RS1000039865 (9:131995953 T>C), RS1000077467 (9:131996203 T>C), RS1000092656 (9:132039707 C>G), RS1000125495 (9:131864698 C>T), RS1000134799 (9:131866352 A>T), RS1000147400 (9:131876629 C>T), RS1000156974 (9:131886252 T>C), RS1000164607 (9:132005109 T>C), RS1000165800 (9:131962233 T>C,G), RS1000183122 (9:132028344 T>C), RS1000195958 (9:132050406 G>T), RS1000218433 (9:131875801 T>C)

Disease associations

OMIM: gene MIM:605044 | disease phenotypes: MIM:619286

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia	Strong	Autosomal recessive
syndromic intellectual disability	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia	Definitive	AR

Mondo (4): neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia (MONDO:0859137), Dravet syndrome (MONDO:0100135), intellectual disability (MONDO:0001071), syndromic intellectual disability (MONDO:0000508)

Orphanet (2): Dravet syndrome (Orphanet:33069), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000012	Urinary urgency
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000463	Anteverted nares
HP:0000518	Cataract
HP:0000527	Long eyelashes
HP:0000592	Blue sclerae
HP:0000664	Synophrys
HP:0000687	Widely spaced teeth
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001332	Dystonia
HP:0002007	Frontal bossing
HP:0002059	Cerebral atrophy
HP:0002236	Frontal upsweep of hair
HP:0002263	Exaggerated cupid’s bow
HP:0002307	Drooling
HP:0002376	Developmental regression
HP:0002553	Highly arched eyebrow
HP:0003429	CNS hypomyelination
HP:0005280	Depressed nasal bridge
HP:0009879	Simplified gyral pattern

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005141_68	Cognitive ability (MTAG)	2.000000e-08
GCST005142_69	Cognitive ability	8.000000e-06
GCST010244_198	Triglyceride levels	1.000000e-08
GCST010273_11	Gout (normal type)	5.000000e-07
GCST90000047_202	Age at first sexual intercourse	2.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004530	triglyceride measurement
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	5
Cisplatin	affects expression, affects cotreatment, decreases expression	5
bisphenol A	decreases expression, decreases methylation	3
Cadmium Chloride	increases palmitoylation, increases expression, decreases reaction, increases abundance	3
sodium arsenite	increases expression	2
dicrotophos	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
benzo(e)pyrene	increases methylation	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression, increases expression	1
Decitabine	affects expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Diazinon	increases methylation	1
Lead	affects expression	1
Methapyrilene	increases methylation	1
Phthalic Acids	increases methylation	1
Piroxicam	affects cotreatment, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Vitamin E	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05044819	PHASE4	ACTIVE_NOT_RECRUITING	Assessment of Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution
NCT06598449	PHASE4	RECRUITING	Assessment of Safety of the Use of Fenfluramine in Children With Dravet Syndrome Under 24 Months of Age
NCT06924827	PHASE4	NOT_YET_RECRUITING	A Study to Investigate the Transition of Children From ‘Artisanal Cannabidiol (CBD) to Epidiolex
NCT07112365	PHASE4	NOT_YET_RECRUITING	The FINTEPLA as an Anti-SUDEP Therapy in Dravet Syndrome Project
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
NCT00098475	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide and Dexamethasone With or Without Thalidomide in Treating Patients With Multiple Myeloma
NCT00114101	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide in Treating Patients With Multiple Myeloma Undergoing Autologous Stem Cell Transplant
NCT00644228	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide and Dexamethasone With or Without Bortezomib in Treating Patients With Previously Untreated Multiple Myeloma
NCT00869206	PHASE3	COMPLETED	Zoledronic Acid in Treating Patients With Metastatic Breast Cancer, Metastatic Prostate Cancer, or Multiple Myeloma With Bone Involvement
NCT02091375	PHASE3	COMPLETED	Antiepileptic Efficacy Study of GWP42003-P in Children and Young Adults With Dravet Syndrome (GWPCARE1)
NCT02174094	PHASE3	WITHDRAWN	Clobazam as Adjunctive Therapy in Paediatric Patients Aged ≥1 to ≤16 Years With Dravet Syndrome
NCT02187809	PHASE3	TERMINATED	Safety and Tolerability of Clobazam as Adjunctive Therapy in Paediatric Patients Aged ≥1 to ≤16 Years With Dravet Syndrome
NCT02224573	PHASE3	COMPLETED	An Open Label Extension Study of Cannabidiol (GWP42003-P) in Children and Adults With Dravet or Lennox-Gastaut Syndromes
NCT02224703	PHASE3	COMPLETED	GWPCARE2 A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P) in Children and Young Adults With Dravet Syndrome
NCT02318563	PHASE3	WITHDRAWN	Cannabidiol Oral Solution as an Adjunctive Therapy for Treatment of Participants With Inadequately Controlled Dravet Syndrome
NCT02682927	PHASE3	COMPLETED	A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) in Children and Young Adults With Dravet Syndrome
NCT02823145	PHASE3	COMPLETED	An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride HCl) Oral Solution in Children and Young Adults With Dravet Syndrome
NCT02926898	PHASE3	COMPLETED	A 2-Part Study to Investigate the Dose-Ranging Safety and Pharmacokinetics, Followed by the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children ≥ 2 Years Old and Young Adults With Dravet Syndrome
NCT03299842	PHASE3	TERMINATED	A Study to Assess the Usability of the Embrace Seizure Detection Watch in Children and Young Adults With Dravet Syndrome
NCT03936777	PHASE3	COMPLETED	A Study to Investigate the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution in Children and Adults With Epileptic Encephalopathy Including Dravet Syndrome and Lennox-Gastaut Syndrome
NCT04462770	PHASE3	RECRUITING	A Study of EPX-100 (Clemizole Hydrochloride) in Participants With Dravet Syndrome
NCT04611438	PHASE3	UNKNOWN	Research on Cognitive Effect of Cannabidiol on Dravet Syndrome and Lennox-Gastaut SyndromeGastaut Syndrome
NCT04940624	PHASE3	COMPLETED	A Study of Soticlestat as an Add-on Therapy in Children and Young Adults With Dravet Syndrome
NCT05163314	PHASE3	TERMINATED	A Study of Soticlestat as an Add-on Therapy in Children and Adults With Dravet Syndrome or Lennox-Gastaut Syndrome
NCT05560282	PHASE3	TERMINATED	Fenfluramine for Adult Dravet Patients
NCT06118255	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Fenfluramine (Hydrochloride) in Infants 1 Year to Less Than 2 Years of Age With Dravet Syndrome
NCT06422377	PHASE3	TERMINATED	A Study Evaluating Soticlestat in Participants With Dravet Syndrome or Lennox-Gastaut Syndrome Who Have Been Exposed to Fenfluramine
NCT06660394	PHASE3	RECRUITING	A Phase 3, Placebo-Controlled Study to Investigate LP352 in Children and Adults With Dravet Syndrome (DS)
NCT06872125	PHASE3	RECRUITING	A Double-blind Study Evaluating the Efficacy, Safety, and Tolerability of Zorevunersen in Patients With Dravet Syndrome
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
NCT00066638	PHASE2	COMPLETED	FR901228 in Treating Patients With Relapsed or Refractory Multiple Myeloma
NCT00088855	PHASE2	COMPLETED	Bortezomib and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients With Previously Untreated Symptomatic Multiple Myeloma
NCT00445692	PHASE2	COMPLETED	Lenalidomide, Dexamethasone, and Clarithromycin in Treating Patients Who Have Undergone Stem Cell Transplant for Multiple Myeloma
NCT00839956	PHASE2	COMPLETED	Bortezomib and Vorinostat in Treating Patients With Multiple Myeloma Who Have Undergone Autologous Stem Cell Transplant
NCT01028716	PHASE2	TERMINATED	Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01251172	PHASE2	WITHDRAWN	RO4929097 After Autologous Stem Cell Transplant in Treating Patients With Multiple Myeloma
NCT01605032	PHASE2	COMPLETED	Busulfan, Melphalan, and Bortezomib Before First-Line Stem Cell Transplant in Treating Patients With Multiple Myeloma