MED17

Summary

MED17 (mediator complex subunit 17, HGNC:2375) is a protein-coding gene on chromosome 11q21, encoding Mediator of RNA polymerase II transcription subunit 17 (Q9NVC6). 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 98.1% 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.

Source: NCBI Gene 9440 — RefSeq curated summary.

At a glance

• Gene–disease (curated): infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly (Strong, GenCC)
• Clinical variants (ClinVar): 660 total — 42 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 18
• Cancer dependency (DepMap): dependent in 98.1% of screened cell lines (common-essential)
• MANE Select transcript: NM_004268

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2375
Approved symbol	MED17
Name	mediator complex subunit 17
Location	11q21
Locus type	gene with protein product
Status	Approved
Aliases	CRSP77, TRAP80, DRIP80, SRB4
Ensembl gene	ENSG00000042429
Ensembl biotype	protein_coding
OMIM	603810
Entrez	9440

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 12 nonsense_mediated_decay, 11 retained_intron, 10 protein_coding

ENST00000251871, ENST00000507258, ENST00000525026, ENST00000525613, ENST00000528786, ENST00000529626, ENST00000530819, ENST00000531920, ENST00000533133, ENST00000533359, ENST00000533367, ENST00000638270, ENST00000638294, ENST00000638487, ENST00000638518, ENST00000638790, ENST00000639189, ENST00000639457, ENST00000639523, ENST00000639596, ENST00000639724, ENST00000640027, ENST00000640077, ENST00000640411, ENST00000640451, ENST00000640473, ENST00000640521, ENST00000640583, ENST00000640804, ENST00000920582, ENST00000920583, ENST00000943466, ENST00000943467

RefSeq mRNA: 1 — MANE Select: NM_004268 NM_004268

CCDS: CCDS8295

Canonical transcript exons

ENST00000251871 — 12 exons

Exon	Start	End
ENSE00000989377	93790574	93790793
ENSE00002174375	93811853	93814963
ENSE00003535228	93788001	93788167
ENSE00003552097	93797535	93797719
ENSE00003559424	93809717	93809876
ENSE00003565044	93793951	93794035
ENSE00003582275	93793728	93793864
ENSE00003610925	93794908	93795060
ENSE00003664987	93801835	93801972
ENSE00003673791	93796410	93796540
ENSE00003678138	93807518	93807635
ENSE00003805858	93784282	93784763

Expression profiles

Bgee: expression breadth ubiquitous, 199 present calls, max score 92.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.1289 / max 238.3430, expressed in 1811 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116243	14.0784	1803
116244	3.8380	1615
116245	1.9510	977
116246	0.2615	126

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	92.15	gold quality
ventricular zone	UBERON:0003053	91.50	gold quality
cortical plate	UBERON:0005343	91.34	gold quality
ganglionic eminence	UBERON:0004023	91.27	gold quality
embryo	UBERON:0000922	91.26	gold quality
calcaneal tendon	UBERON:0003701	90.64	gold quality
left ovary	UBERON:0002119	89.46	gold quality
right ovary	UBERON:0002118	88.54	gold quality
endocervix	UBERON:0000458	87.80	gold quality
stromal cell of endometrium	CL:0002255	87.62	gold quality
granulocyte	CL:0000094	87.53	gold quality
body of uterus	UBERON:0009853	87.35	gold quality
ovary	UBERON:0000992	87.04	gold quality
smooth muscle tissue	UBERON:0001135	86.80	gold quality
cerebellar hemisphere	UBERON:0002245	86.53	gold quality
right uterine tube	UBERON:0001302	86.52	gold quality
left uterine tube	UBERON:0001303	86.51	gold quality
adrenal tissue	UBERON:0018303	86.48	gold quality
colonic epithelium	UBERON:0000397	86.45	gold quality
cerebellar cortex	UBERON:0002129	86.33	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.26	gold quality
tibial nerve	UBERON:0001323	86.15	gold quality
ectocervix	UBERON:0012249	86.15	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.07	gold quality
right lobe of thyroid gland	UBERON:0001119	85.88	gold quality
left lobe of thyroid gland	UBERON:0001120	85.61	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	85.57	gold quality
leukocyte	CL:0000738	85.55	gold quality
lower esophagus muscularis layer	UBERON:0035833	85.49	gold quality
lower esophagus	UBERON:0013473	85.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

100 targeting MED17, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-6124	99.87	69.78	3551

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 8)

• the p. L371P mutation in MED17 is a founder mutation in the Caucasus Jewish community and that homozygosity for this mutation is associated with infantile cerebral and cerebellar atrophy with poor myelination. (PMID:20950787)
• Studies indicate that the activation domain of p53 (p53AD) binds directly to the MED17 subunit of Mediator, whereas the p53 C-terminal domain (p53CTD) binds the MED1 subunit. (PMID:21326907)
• TRAP80 is a selective regulator of hepatic lipogenesis and is required for LXR-dependent SREBP-1c activation. (PMID:25437875)
• These findings suggest that hMED17 may play essential roles in switching between transcription and nucleotide excision repair. (PMID:25482373)
• The cell polarity kinase Par1b/MARK2 activation selects specific NF-kB transcripts via phosphorylation of core mediator Med17/TRAP80. (PMID:33596087)
• Delineation of the phenotype of MED17-related disease in Caucasus-Jewish families. (PMID:33756211)
• Increased unfolded protein responses caused by MED17 mutations. (PMID:34392449)
• An expansion of phenotype: novel homozygous variant in the MED17 identified in patients with progressive microcephaly and global developmental delay. (PMID:36508181)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	med17	ENSDARG00000006345
mus_musculus	Med17	ENSMUSG00000031935
rattus_norvegicus	Med17	ENSRNOG00000010496
drosophila_melanogaster	MED17	FBGN0038578
caenorhabditis_elegans		WBGENE00007017

Protein

Protein identifiers

Mediator of RNA polymerase II transcription subunit 17 — Q9NVC6 (reviewed: Q9NVC6)

Alternative names: Activator-recruited cofactor 77 kDa component, Cofactor required for Sp1 transcriptional activation subunit 6, Mediator complex subunit 17, Thyroid hormone receptor-associated protein complex 80 kDa component, Transcriptional coactivator CRSP77, Vitamin D3 receptor-interacting protein complex 80 kDa component

All UniProt accessions (16): A0A1W2PNF3, A0A1W2PNW7, A0A1W2PPC8, A0A1W2PPJ7, A0A1W2PPP8, A0A1W2PQ48, A0A1W2PQE4, A0A1W2PR99, A0A1W2PRS0, A0A1W2PRX4, A0A1W2PS27, A0A1W2PS69, Q9NVC6, E9PJZ4, E9PKQ4, E9PM72

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. Interacts with GATA1 and PPARG. 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. Interacts with STAT2.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous.

Disease relevance. Microcephaly, postnatal progressive, with seizures and brain atrophy (MCPHSBA) [MIM:613668] A disorder characterized by postnatal progressive microcephaly and severe developmental retardation associated with cerebral and cerebellar atrophy. Infants manifest swallowing difficulties leading to failure to thrive, jitteriness, poor visual fixation, truncal arching, seizures. There is no acquisition of developmental milestones and patients suffer from marked spasticity and profound retardation. Progressive microcephaly becomes evident few months after birth. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be due to intron retention.

Similarity. Belongs to the Mediator complex subunit 17 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NVC6-1	1	yes
Q9NVC6-2	2

RefSeq proteins (1): NP_004259* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019313	Mediator_Med17	Family

Pfam: PF10156

UniProt features (50 total): strand 22, helix 13, sequence conflict 5, turn 3, sequence variant 3, splice variant 2, chain 1, region of interest 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-Q9NVC6-F1	78.95	0.37

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: 208 (showing top): REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, GCM_GSPT1, GOBP_POSITIVE_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GCM_ZNF198, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GOBP_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GCM_NUMA1, GOBP_MAINTENANCE_OF_CELL_NUMBER, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_TRANSCRIPTION_INITIATION_AT_RNA_POLYMERASE_II_PROMOTER

GO Biological Process (9): 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), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), RNA polymerase II preinitiation complex assembly (GO:0051123), positive regulation of transcription initiation by RNA polymerase II (GO:0060261)

GO Molecular Function (6): transcription coregulator activity (GO:0003712), transcription coactivator activity (GO:0003713), nuclear vitamin D receptor binding (GO:0042809), nuclear thyroid hormone receptor binding (GO:0046966), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515)

GO Cellular Component (7): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), membrane (GO:0016020), 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	3
regulation of DNA-templated transcription	2
positive regulation of transcription by RNA polymerase II	2
positive regulation of DNA-templated transcription	2
transcription initiation at RNA polymerase II promoter	2
nuclear receptor binding	2
cellular anatomical structure	2
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
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription preinitiation complex assembly	1
regulation of transcription initiation by RNA polymerase II	1
positive regulation of DNA-templated transcription initiation	1
transcription regulator activity	1
transcription coregulator activity	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
nuclear lumen	1
protein-containing complex	1
core mediator complex	1
nuclear protein-containing complex	1
RNA polymerase II transcription regulator complex	1

Protein interactions and networks

STRING

2150 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MED17	MED8	Q96G25	996
MED17	MED6	O75586	995
MED17	MED11	Q9P086	995
MED17	MED22	Q15528	994
MED17	MED20	Q9H944	990
MED17	MED14	O60244	988
MED17	MED27	Q6P2C8	977
MED17	MED12	Q93074	976
MED17	MED10	Q9BTT4	976
MED17	MED30	Q96HR3	956
MED17	MED31	Q9Y3C7	952
MED17	MED18	Q9BUE0	950
MED17	MED19	A0JLT2	947
MED17	MED21	Q13503	946
MED17	MED7	O43513	938

IntAct

179 interactions, top by confidence:

A	B	Type	Score
FOS	JUN	psi-mi:“MI:0914”(association)	0.980
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
MED10	MED19	psi-mi:“MI:0915”(physical association)	0.910
MED10	MED8	psi-mi:“MI:0914”(association)	0.910
CDK8	MED14	psi-mi:“MI:0914”(association)	0.900
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
MED10	MED24	psi-mi:“MI:0914”(association)	0.870
MED10	MED6	psi-mi:“MI:0914”(association)	0.870
MED17	MED22	psi-mi:“MI:0914”(association)	0.860
MED17	MED22	psi-mi:“MI:0915”(physical association)	0.860
MED22	MED17	psi-mi:“MI:0915”(physical association)	0.860

BioGRID (418): MED17 (Affinity Capture-MS), MED17 (Affinity Capture-MS), MED17 (Affinity Capture-MS), MED17 (Affinity Capture-MS), MED17 (Affinity Capture-MS), MED17 (Affinity Capture-MS), MED17 (Affinity Capture-MS), MED17 (Affinity Capture-MS), MED17 (Affinity Capture-MS), MED12 (Co-fractionation), MED13 (Co-fractionation), MED16 (Co-fractionation), MED17 (Co-fractionation), MED17 (Co-fractionation), MED17 (Co-fractionation)

ESM2 similar proteins: B0DOB4, D4A4K3, F4K460, F6U5F9, O75182, O75448, O88480, Q08BY1, Q08D69, Q0VFR9, Q17JT4, Q28DG8, Q2I0E5, Q2TBN7, Q3B8G8, Q4V8B3, Q566H4, Q5BIR6, Q5F3M0, Q5R6U8, Q5U1Z0, Q5U249, Q5XHA1, Q5ZID1, Q62141, Q642Q3, Q6DFL5, Q6DIK0, Q6GLY5, Q6NY52, Q6P2C8, Q6PFL0, Q6Q7J5, Q7PVZ2, Q7ZXA8, Q8BMG7, Q8C456, Q8CDJ3, Q8CJF7, Q8QZV7

Diamond homologs: Q08BY1, Q0VFR9, Q17JT4, Q5BIR6, Q5ZID1, Q7PVZ2, Q8VCD5, Q9NVC6, Q9VEC1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MED17	“form complex”	“Core mediator complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 114 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	26	67.4×	2e-40
FGFR2 mutant receptor activation	6	60.1×	3e-09
Signaling by FGFR2 IIIa TM	7	55.4×	2e-10
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	10	53.7×	3e-14
RNA Pol II CTD phosphorylation and interaction with CE	10	53.7×	3e-14
RSV-host interactions	26	53.5×	1e-37
Adipogenesis	26	53.5×	1e-37
Abortive elongation of HIV-1 transcript in the absence of Tat	8	52.3×	2e-11

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	22	69.7×	1e-33
positive regulation of transcription initiation by RNA polymerase II	24	68.7×	2e-36
RNA polymerase II preinitiation complex assembly	23	65.8×	2e-34
transcription initiation at RNA polymerase II promoter	9	35.5×	4e-10
somatic stem cell population maintenance	9	23.5×	1e-08
mRNA transcription by RNA polymerase II	5	17.4×	5e-04
transcription by RNA polymerase II	18	13.4×	2e-13
protein ubiquitination	11	4.8×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	36
Uncertain significance	164
Likely benign	335
Benign	46

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070546	NM_004268.5(MED17):c.999_1000del (p.Gln334fs)	Pathogenic
1071581	NM_004268.5(MED17):c.1200del (p.Phe400fs)	Pathogenic
1072194	NM_004268.5(MED17):c.1150A>T (p.Lys384Ter)	Pathogenic
1072802	NM_004268.5(MED17):c.1087_1088insA (p.Cys363Ter)	Pathogenic
1076891	NC_000011.9:g.(?93521157)(93521343_?)del	Pathogenic
1076892	NC_000011.9:g.(?93529566)(93535148_?)del	Pathogenic
1355674	NM_004268.5(MED17):c.159_162del (p.Gly54fs)	Pathogenic
1360484	NM_004268.5(MED17):c.1210A>T (p.Arg404Ter)	Pathogenic
1361805	NM_004268.5(MED17):c.866dup (p.His290fs)	Pathogenic
1374712	NM_004268.5(MED17):c.1054A>T (p.Lys352Ter)	Pathogenic
1396500	NM_004268.5(MED17):c.788_789dup (p.Gln264fs)	Pathogenic
1422917	NM_004268.5(MED17):c.1648_1649dup (p.Ser550fs)	Pathogenic
1438359	NM_004268.5(MED17):c.657del (p.His219fs)	Pathogenic
1459566	NC_000011.9:g.(?93517670)(93517939_?)del	Pathogenic
1460305	NC_000011.9:g.(?93529711)(93539976_?)del	Pathogenic
1908309	NM_004268.5(MED17):c.790C>T (p.Gln264Ter)	Pathogenic
1996383	NM_004268.5(MED17):c.490del (p.Ala164fs)	Pathogenic
2001262	NM_004268.5(MED17):c.1223C>A (p.Ser408Ter)	Pathogenic
2030536	NM_004268.5(MED17):c.784C>T (p.Gln262Ter)	Pathogenic
2033551	NM_004268.5(MED17):c.1549C>T (p.Gln517Ter)	Pathogenic
2042198	NM_004268.5(MED17):c.415C>T (p.Gln139Ter)	Pathogenic
2131080	NM_004268.5(MED17):c.172G>T (p.Glu58Ter)	Pathogenic
2153631	NM_004268.5(MED17):c.1637G>A (p.Trp546Ter)	Pathogenic
2715833	NM_004268.5(MED17):c.646_649del (p.Phe216fs)	Pathogenic
2719707	NM_004268.5(MED17):c.924dup (p.Ala309fs)	Pathogenic
2749801	NM_004268.5(MED17):c.1576del (p.Leu526fs)	Pathogenic
2813000	NM_004268.5(MED17):c.1552G>T (p.Glu518Ter)	Pathogenic
2818888	NM_004268.5(MED17):c.1063C>T (p.Gln355Ter)	Pathogenic
2818918	NM_004268.5(MED17):c.46G>T (p.Glu16Ter)	Pathogenic
2847768	NM_004268.5(MED17):c.549dup (p.Asn184fs)	Pathogenic

SpliceAI

1494 predictions. Top by Δscore:

Variant	Effect	Δscore
11:93784759:GGAAG:G	donor_gain	1.0000
11:93784760:GAAGG:G	donor_gain	1.0000
11:93784761:A:T	donor_gain	1.0000
11:93784764:GTAAG:G	donor_loss	1.0000
11:93784765:T:G	donor_loss	1.0000
11:93787999:A:AG	acceptor_gain	1.0000
11:93788000:G:GG	acceptor_gain	1.0000
11:93788000:GGA:G	acceptor_gain	1.0000
11:93788000:GGAGT:G	acceptor_gain	1.0000
11:93788163:AACAG:A	donor_loss	1.0000
11:93788164:ACAG:A	donor_loss	1.0000
11:93788165:CAGG:C	donor_loss	1.0000
11:93788166:AG:A	donor_loss	1.0000
11:93788167:GG:G	donor_loss	1.0000
11:93788168:G:GA	donor_loss	1.0000
11:93788169:T:A	donor_loss	1.0000
11:93790794:GTAT:G	donor_loss	1.0000
11:93790795:T:A	donor_loss	1.0000
11:93793709:A:AG	acceptor_gain	1.0000
11:93793710:T:G	acceptor_gain	1.0000
11:93793715:A:AG	acceptor_gain	1.0000
11:93793716:A:G	acceptor_gain	1.0000
11:93793717:T:G	acceptor_gain	1.0000
11:93793718:A:AG	acceptor_gain	1.0000
11:93793719:C:G	acceptor_gain	1.0000
11:93793720:A:AG	acceptor_gain	1.0000
11:93793721:A:G	acceptor_gain	1.0000
11:93793723:A:AG	acceptor_gain	1.0000
11:93793723:ATTAG:A	acceptor_gain	1.0000
11:93793743:ATCAT:A	acceptor_gain	1.0000

AlphaMissense

4297 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:93784644:C:A	A44D	1.000
11:93788033:T:A	W95R	1.000
11:93788033:T:C	W95R	1.000
11:93790716:T:C	L187P	1.000
11:93790736:T:A	W194R	1.000
11:93790736:T:C	W194R	1.000
11:93790769:G:A	G205R	1.000
11:93790769:G:C	G205R	1.000
11:93790770:G:A	G205E	1.000
11:93790776:T:C	L207P	1.000
11:93793824:T:A	V245D	1.000
11:93794980:T:C	L311P	1.000
11:93809754:C:A	A541D	1.000
11:93809768:T:A	W546R	1.000
11:93809768:T:C	W546R	1.000
11:93784632:T:C	L40P	0.999
11:93784653:T:A	I47K	0.999
11:93784658:T:C	F49L	0.999
11:93784659:T:C	F49S	0.999
11:93784660:C:A	F49L	0.999
11:93784660:C:G	F49L	0.999
11:93788027:T:A	W93R	0.999
11:93788027:T:C	W93R	0.999
11:93788035:G:C	W95C	0.999
11:93788035:G:T	W95C	0.999
11:93788067:T:C	L106P	0.999
11:93788082:T:A	V111D	0.999
11:93788085:T:C	L112P	0.999
11:93788090:G:T	D114Y	0.999
11:93788091:A:C	D114A	0.999

dbSNP variants (sampled 300 via entrez): RS1000015695 (11:93808527 T>C), RS1000055516 (11:93798149 C>T), RS1000055793 (11:93785120 G>C), RS1000112556 (11:93810627 A>G), RS1000128289 (11:93808192 C>T), RS1000199567 (11:93785130 A>G), RS1000302805 (11:93800817 T>C), RS1000313177 (11:93784839 TG>T,TGG), RS1000352588 (11:93814105 G>C), RS1000353449 (11:93813948 C>T), RS1000464401 (11:93789275 T>A), RS1000513771 (11:93813349 C>G), RS1000630162 (11:93789620 T>C), RS1000675545 (11:93790897 A>G), RS1000716483 (11:93801022 A>G,T)

Disease associations

OMIM: gene MIM:603810 | disease phenotypes: MIM:613668

GenCC curated gene-disease

Disease	Classification	Inheritance
infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly	Strong	Autosomal recessive

Mondo (3): infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly (MONDO:0013351), microcephaly (MONDO:0001149), intellectual disability (MONDO:0001071)

Orphanet (2): Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly (Orphanet:402364), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

18 total (19 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0002015	Dysphagia
HP:0002169	Clonus
HP:0002188	Delayed CNS myelination
HP:0002365	Hypoplasia of the brainstem
HP:0002506	Diffuse cerebral atrophy
HP:0002521	Hypsarrhythmia
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0005484	Secondary microcephaly
HP:0011968	Feeding difficulties
HP:0012695	Decreased thalamic volume
HP:0000252	Microcephaly

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	5
methylmercuric chloride	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
TAK-243	increases sumoylation	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	affects methylation	1
cobaltous chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases expression	1
Caffeine	increases phosphorylation	1
Carbamazepine	affects expression	1
Demecolcine	increases expression	1
Diclofenac	affects expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Lead	affects expression	1
Oxygen	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Thimerosal	increases expression	1
Tobacco Smoke Pollution	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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
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
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)
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities