SEMA6B

Summary

SEMA6B (semaphorin 6B, HGNC:10739) is a protein-coding gene on chromosome 19p13.3, encoding Semaphorin-6B (Q9H3T3). Functions as a cell surface repellent for mossy fibers of developing neurons in the hippocampus where it plays a role in axon guidance.

This gene encodes a member of the semaphorin family, a group of proteins characterized by the presence of a conserved semaphorin (sema) domain. Whereas some semaphorins are transmembrane proteins, others are secreted. Semaphorins play a major role in axon guidance. The protein encoded by this gene may be involved in both peripheral and central nervous system development.

Source: NCBI Gene 10501 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progressive myoclonus epilepsy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 346 total — 11 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 17
• MANE Select transcript: NM_032108

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10739
Approved symbol	SEMA6B
Name	semaphorin 6B
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	semaZ, SEMA-VIB, SEM-SEMA-Z
Ensembl gene	ENSG00000167680
Ensembl biotype	protein_coding
OMIM	608873
Entrez	10501

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000586582, ENST00000586965, ENST00000589889, ENST00000676793, ENST00000677828, ENST00000913565

RefSeq mRNA: 1 — MANE Select: NM_032108 NM_032108

CCDS: CCDS12131

Canonical transcript exons

ENST00000586582 — 17 exons

Exon	Start	End
ENSE00001115538	4555988	4556089
ENSE00001115540	4558026	4558149
ENSE00001115542	4550799	4550930
ENSE00001115543	4556951	4557013
ENSE00001115544	4546216	4546274
ENSE00001115545	4555474	4555564
ENSE00001115547	4548027	4548173
ENSE00001115548	4554976	4555095
ENSE00001115549	4557163	4557223
ENSE00001115552	4552422	4552639
ENSE00001115554	4548263	4548445
ENSE00001115556	4550123	4550272
ENSE00001115557	4554388	4554476
ENSE00002825212	4558337	4558489
ENSE00002970714	4559530	4559684
ENSE00003661644	4546392	4546469
ENSE00004035139	4542593	4544529

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 95.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.0623 / max 736.3967, expressed in 1134 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178480	8.7776	913
178476	7.0193	440
178475	4.6018	314
178477	1.4341	261
178474	0.5581	167
178473	0.3030	126
178472	0.1986	107
178479	0.1698	89

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	95.03	gold quality
anterior cingulate cortex	UBERON:0009835	94.80	gold quality
cingulate cortex	UBERON:0003027	94.71	gold quality
prefrontal cortex	UBERON:0000451	93.93	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.43	gold quality
amygdala	UBERON:0001876	92.23	gold quality
cortical plate	UBERON:0005343	92.20	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.96	gold quality
nucleus accumbens	UBERON:0001882	91.80	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.54	gold quality
frontal cortex	UBERON:0001870	91.17	gold quality
neocortex	UBERON:0001950	91.06	gold quality
cerebellar hemisphere	UBERON:0002245	90.95	gold quality
caudate nucleus	UBERON:0001873	90.91	gold quality
cerebellar cortex	UBERON:0002129	90.86	gold quality
apex of heart	UBERON:0002098	89.54	gold quality
putamen	UBERON:0001874	89.46	gold quality
cerebral cortex	UBERON:0000956	89.24	gold quality
cerebellum	UBERON:0002037	89.23	gold quality
telencephalon	UBERON:0001893	88.83	gold quality
triceps brachii	UBERON:0001509	88.63	gold quality
Ammon’s horn	UBERON:0001954	87.56	gold quality
forebrain	UBERON:0001890	87.10	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.91	gold quality
spleen	UBERON:0002106	86.81	gold quality
brain	UBERON:0000955	86.55	gold quality
gluteal muscle	UBERON:0002000	86.23	gold quality
left adrenal gland cortex	UBERON:0035825	86.09	gold quality
omental fat pad	UBERON:0010414	86.00	gold quality
temporal lobe	UBERON:0001871	85.98	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-9435	yes	2760.92
E-MTAB-6308	yes	1842.04
E-MTAB-8142	yes	113.11
E-CURD-88	yes	46.62
E-HCAD-1	yes	43.49
E-MTAB-6701	yes	30.79
E-HCAD-9	yes	23.21
E-GEOD-137537	yes	16.05
E-ANND-3	yes	13.93
E-HCAD-10	yes	7.99
E-GEOD-134144	no	2244.55
E-MTAB-7316	no	1188.56
E-HCAD-8	no	36.07

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RXRA

miRNA regulators (miRDB)

39 targeting SEMA6B, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-129-1-3P	98.86	68.41	779
HSA-MIR-129-2-3P	98.86	68.41	779
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-3974	96.56	66.22	928
HSA-MIR-6762-5P	96.55	64.62	972
HSA-MIR-6845-5P	96.55	64.65	969

Literature-anchored findings (GeneRIF, showing 9)

• Gene SEMA6B is strongly down regulated by peroxisome proliferator-activated receptors. (PMID:15177567)
• states a clear relation among breast cancer and SEMA6B expression; moreover we describe for the first time the SEMA6Ba protein and report here the analysis of SEMA6Ba RNA messenger, the protein expression and the cellular localization (PMID:23665584)
• Semaphorin 6B is related to tumour differentiation and metastasis in vivo, and tumour cell migration, adhesion and invasion in vitro. (PMID:23781008)
• Heterozygous truncating variants in the NMD(+) region of SEMA6B are observed in general populations. (PMID:32169168)
• Genome-Wide CRISPR Screen Identifies Semaphorin 6A and 6B as Receptors for Paeniclostridium sordellii Toxin TcsL. (PMID:32302524)
• Aberrant expression of semaphorin 6B affects cell phenotypes in thyroid carcinoma by activating the Notch signalling pathway. (PMID:33125690)
• A Frameshift Variant in the SEMA6B Gene Causes Global Developmental Delay and Febrile Seizures. (PMID:34110594)
• SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance. (PMID:35604360)
• Progressive myoclonus epilepsies due to SEMA6B mutations. New variants and appraisal of published phenotypes. (PMID:36719163)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sema6ba	ENSDARG00000036626
danio_rerio	sema6bb	ENSDARG00000061976
mus_musculus	Sema6b	ENSMUSG00000001227
rattus_norvegicus	Sema6b	ENSRNOG00000045998

Paralogs (19): SEMA3F (ENSG00000001617), SEMA3G (ENSG00000010319), SEMA3B (ENSG00000012171), SEMA3A (ENSG00000075213), SEMA3C (ENSG00000075223), SEMA5B (ENSG00000082684), SEMA6A (ENSG00000092421), SEMA4G (ENSG00000095539), SEMA5A (ENSG00000112902), SEMA4F (ENSG00000135622), SEMA6D (ENSG00000137872), SEMA7A (ENSG00000138623), SEMA6C (ENSG00000143434), SEMA3D (ENSG00000153993), SEMA4C (ENSG00000168758), SEMA3E (ENSG00000170381), SEMA4B (ENSG00000185033), SEMA4D (ENSG00000187764), SEMA4A (ENSG00000196189)

Protein

Protein identifiers

Semaphorin-6B — Q9H3T3 (reviewed: Q9H3T3)

Alternative names: Semaphorin-Z

All UniProt accessions (2): A0A7I2V374, Q9H3T3

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a cell surface repellent for mossy fibers of developing neurons in the hippocampus where it plays a role in axon guidance. May function through the PLXNA4 receptor expressed by mossy cell axons. (Microbial infection) Acts as a receptor for P.sordellii toxin TcsL in the in the vascular endothelium.

Subunit / interactions. (Microbial infection) Interacts with P.sordellii toxin TcsL; semaphorins SEMA6A and SEMA6B constitute the major host receptors for TcsL in the vascular endothelium.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in the brain in GABAergic neurons.

Disease relevance. Epilepsy, progressive myoclonic 11 (EPM11) [MIM:618876] A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM11 is an autosomal dominant form. Clinical features include normal or mildly delayed early development, developmental regression after seizures onset, inability to walk, severely impaired intellectual development, poor or absent speech, spasticity, ataxia, and intention tremor. Brain imaging shows cerebellar atrophy in some patients. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the semaphorin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H3T3-1	1	yes
Q9H3T3-3	2

RefSeq proteins (1): NP_115484* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001627	Semap_dom	Domain
IPR002165	Plexin_repeat	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR027231	Semaphorin	Family
IPR036352	Semap_dom_sf	Homologous_superfamily

Pfam: PF01403, PF01437

UniProt features (30 total): disulfide bond 8, glycosylation site 7, region of interest 3, compositionally biased region 2, topological domain 2, splice variant 2, signal peptide 1, chain 1, modified residue 1, sequence conflict 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3T3-F1	74.81	0.52

Functional residue map

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

Post-translational modifications (1): 665

Disulfide bonds (8): 116–126, 144–153, 267–378, 292–337, 486–517, 526–544, 532–578, 536–552

Glycosylation sites (7): 74, 155, 167, 291, 386, 441, 462

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 161 (showing top): WANG_CLIM2_TARGETS_UP, GOBP_NEUROGENESIS, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, MAYBURD_RESPONSE_TO_L663536_UP, GOBP_TAXIS, GOBP_MESENCHYMAL_CELL_DIFFERENTIATION, GOBP_HIPPOCAMPUS_DEVELOPMENT, GOBP_PALLIUM_DEVELOPMENT, TGANTCA_AP1_C, GOBP_HEAD_DEVELOPMENT, PU1_Q6, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, GOBP_MESENCHYME_DEVELOPMENT, GOBP_CELL_PROJECTION_ORGANIZATION

GO Biological Process (9): neural crest cell migration (GO:0001755), axon guidance (GO:0007411), central nervous system development (GO:0007417), hippocampus development (GO:0021766), positive regulation of cell migration (GO:0030335), semaphorin-plexin signaling pathway (GO:0071526), nervous system development (GO:0007399), cell differentiation (GO:0030154), negative chemotaxis (GO:0050919)

GO Molecular Function (3): semaphorin receptor binding (GO:0030215), chemorepellent activity (GO:0045499), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	2
neural crest cell development	1
mesenchymal cell migration	1
axonogenesis	1
neuron projection guidance	1
nervous system development	1
pallium development	1
limbic system development	1
anatomical structure development	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
cell surface receptor signaling pathway	1
cellular developmental process	1
chemotaxis	1
signaling receptor binding	1
receptor ligand activity	1
negative chemotaxis	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

632 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEMA6B	PLXNA2	O75051	965
SEMA6B	PLXNA4	Q9HCM2	844
SEMA6B	EVL	Q9UI08	833
SEMA6B	PLXNA3	P51805	748
SEMA6B	NRP2	O60462	635
SEMA6B	SRC	P12931	604
SEMA6B	PLXNB1	O43157	574
SEMA6B	PLXND1	Q9Y4D7	571
SEMA6B	ZYX	Q15942	547
SEMA6B	PPARA	Q07869	536
SEMA6B	PLXNA1	Q9UIW2	511
SEMA6B	VASP	P50552	503
SEMA6B	NRP1	O14786	481
SEMA6B	PRICKLE2	Q7Z3G6	433
SEMA6B	CELSR2	Q9HCU4	421

IntAct

48 interactions, top by confidence:

A	B	Type	Score
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
	SEMA6B	psi-mi:“MI:0407”(direct interaction)	0.440
PCDHB3	ESYT2	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-G	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
KLRD1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-DQA1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
LY86	TMEM131L	psi-mi:“MI:0914”(association)	0.350
NRG1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
PTCH1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ASIC4	TMEM131L	psi-mi:“MI:0914”(association)	0.350
IL5RA	POTEF	psi-mi:“MI:0914”(association)	0.350
LCN6	POTEF	psi-mi:“MI:0914”(association)	0.350
TMEM87A	POTEF	psi-mi:“MI:0914”(association)	0.350
LYPD4	POTEF	psi-mi:“MI:0914”(association)	0.350
DNAJB9	POTEF	psi-mi:“MI:0914”(association)	0.350
ISLR		psi-mi:“MI:0914”(association)	0.350
MFAP4	QSOX1	psi-mi:“MI:0914”(association)	0.350
PDGFRA	QSOX1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
CST9L	QSOX1	psi-mi:“MI:0914”(association)	0.350
DNASE1L1	QSOX1	psi-mi:“MI:0914”(association)	0.350
FMOD	QSOX1	psi-mi:“MI:0914”(association)	0.350
SDF2L1	MANBA	psi-mi:“MI:0914”(association)	0.350
C1QB	MANBA	psi-mi:“MI:0914”(association)	0.350

BioGRID (42): SEMA6B (Affinity Capture-RNA), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS), SEMA6B (Affinity Capture-MS)

ESM2 similar proteins: A5PJM7, A6QL63, A7YY62, A7Z026, B2RYF1, E9PV86, O35393, O54951, O70141, O75864, P42229, P42230, P42231, P51692, Q15768, Q29RM4, Q3SZB3, Q3U2I3, Q3UFK8, Q5R5M3, Q5R8V2, Q5U2R3, Q5ZJA4, Q5ZJB7, Q66H54, Q6DN14, Q6GQW0, Q6IA17, Q6ZN54, Q6ZUT9, Q7Z6G3, Q7Z6J6, Q86VR8, Q8BKR5, Q8N5X7, Q8N612, Q8NBT3, Q8TBP0, Q8TF64, Q8WXS5

Diamond homologs: A7MB70, D3ZTD8, O08665, O09126, O15041, O35464, O42236, O42237, O88632, O95025, O95754, P70275, Q13214, Q13275, Q13591, Q14563, Q17330, Q24322, Q24323, Q26473, Q26972, Q4LFA9, Q5EA85, Q5R7F5, Q5RE75, Q60519, Q62177, Q62178, Q62179, Q62181, Q62217, Q63548, Q64151, Q76KF0, Q8BH34, Q8NFY4, Q90607, Q90663, Q90665, Q92854

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 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
Interferon gamma signaling	6	16.4×	4e-04
Neutrophil degranulation	9	4.5×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
adaptive immune response	7	10.3×	6e-04
immune response	7	5.8×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	14
Uncertain significance	215
Likely benign	70
Benign	13

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1316022	NM_032108.4(SEMA6B):c.1930del (p.Ala644fs)	Pathogenic
1321016	NM_032108.4(SEMA6B):c.1958del (p.Arg653fs)	Pathogenic
1334134	NM_032108.4(SEMA6B):c.1966G>T (p.Glu656Ter)	Pathogenic
2429390	NM_032108.4(SEMA6B):c.2000_2015del (p.Gly667fs)	Pathogenic
2579316	NM_032108.4(SEMA6B):c.1993del (p.Arg665fs)	Pathogenic
3253144	NM_032108.4(SEMA6B):c.2056C>T (p.Gln686Ter)	Pathogenic
3773719	NM_032108.4(SEMA6B):c.2067_2070delinsAGCA (p.Trp689_Ala690delinsTer)	Pathogenic
4081865	NM_032108.4(SEMA6B):c.1957del (p.Arg653fs)	Pathogenic
4540008	NM_032108.4(SEMA6B):c.2023del (p.Val675fs)	Pathogenic
872932	NM_032108.4(SEMA6B):c.1950_1969dup (p.Arg657fs)	Pathogenic
872933	NM_032108.4(SEMA6B):c.1976_1982del (p.Ala659fs)	Pathogenic
1066363	NM_032108.4(SEMA6B):c.2125A>G (p.Thr709Ala)	Likely pathogenic
1334195	NM_032108.4(SEMA6B):c.2138C>T (p.Thr713Met)	Likely pathogenic
1334404	NM_032108.4(SEMA6B):c.547G>C (p.Val183Leu)	Likely pathogenic
1339477	NM_032108.4(SEMA6B):c.481C>G (p.Leu161Val)	Likely pathogenic
1526211	NM_032108.4(SEMA6B):c.1534_1537del (p.Ala512fs)	Likely pathogenic
2430274	NM_032108.4(SEMA6B):c.2086C>T (p.Gln696Ter)	Likely pathogenic
2433296	NM_032108.4(SEMA6B):c.1739-2A>G	Likely pathogenic
3775309	NM_032108.4(SEMA6B):c.1977_1978delinsCT (p.Gln660Ter)	Likely pathogenic
3777724	NM_032108.4(SEMA6B):c.1680-2A>G	Likely pathogenic
4077496	NM_032108.4(SEMA6B):c.1951del (p.Val651fs)	Likely pathogenic
4293051	NM_032108.4(SEMA6B):c.1467dup (p.Gly490fs)	Likely pathogenic
4293230	NM_032108.4(SEMA6B):c.1988_1991del (p.Gly663fs)	Likely pathogenic
4540041	NM_032108.4(SEMA6B):c.2025del (p.Pro677fs)	Likely pathogenic
987384	NM_032108.4(SEMA6B):c.2067G>A (p.Trp689Ter)	Likely pathogenic

SpliceAI

2841 predictions. Top by Δscore:

Variant	Effect	Δscore
19:4544526:AGTC:A	acceptor_gain	1.0000
19:4544527:GTC:G	acceptor_gain	1.0000
19:4544528:TC:T	acceptor_gain	1.0000
19:4544529:CC:C	acceptor_gain	1.0000
19:4544530:C:CA	acceptor_loss	1.0000
19:4544530:C:CC	acceptor_gain	1.0000
19:4544531:T:C	acceptor_loss	1.0000
19:4544535:C:CT	acceptor_gain	1.0000
19:4544535:C:T	acceptor_gain	1.0000
19:4544536:G:T	acceptor_gain	1.0000
19:4546211:CTCA:C	donor_loss	1.0000
19:4546212:TCAC:T	donor_loss	1.0000
19:4546213:CAC:C	donor_loss	1.0000
19:4546214:A:C	donor_loss	1.0000
19:4546215:C:G	donor_loss	1.0000
19:4546273:CT:C	acceptor_gain	1.0000
19:4546275:C:CC	acceptor_gain	1.0000
19:4548023:TCA:T	donor_loss	1.0000
19:4548025:A:AC	donor_gain	1.0000
19:4548026:C:CC	donor_gain	1.0000
19:4548026:CTT:C	donor_gain	1.0000
19:4548169:CACAC:C	acceptor_gain	1.0000
19:4548170:ACAC:A	acceptor_gain	1.0000
19:4548171:CAC:C	acceptor_gain	1.0000
19:4548171:CACC:C	acceptor_gain	1.0000
19:4548172:AC:A	acceptor_gain	1.0000
19:4548173:CC:C	acceptor_gain	1.0000
19:4548174:C:CC	acceptor_gain	1.0000
19:4548174:CT:C	acceptor_loss	1.0000
19:4548175:T:A	acceptor_loss	1.0000

AlphaMissense

5661 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:4550834:C:A	W362C	1.000
19:4550834:C:G	W362C	1.000
19:4550836:A:G	W362R	1.000
19:4550836:A:T	W362R	1.000
19:4552550:C:A	K287N	1.000
19:4552550:C:G	K287N	1.000
19:4552565:C:A	W282C	1.000
19:4552565:C:G	W282C	1.000
19:4552567:A:G	W282R	1.000
19:4552567:A:T	W282R	1.000
19:4554998:T:A	K220N	1.000
19:4554998:T:G	K220N	1.000
19:4555050:T:A	D203V	1.000
19:4555061:G:C	F199L	1.000
19:4555061:G:T	F199L	1.000
19:4555062:A:C	F199C	1.000
19:4555063:A:G	F199L	1.000
19:4555065:T:A	D198V	1.000
19:4555065:T:G	D198A	1.000
19:4555066:C:G	D198H	1.000
19:4555514:G:C	C174W	1.000
19:4555516:A:G	C174R	1.000
19:4555527:C:T	G170D	1.000
19:4556000:G:C	C153W	1.000
19:4556001:C:G	C153S	1.000
19:4556001:C:T	C153Y	1.000
19:4556002:A:G	C153R	1.000
19:4556002:A:T	C153S	1.000
19:4556027:G:C	C144W	1.000
19:4556028:C:T	C144Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000014149 (19:4542755 G>A,C), RS1000105664 (19:4556822 G>A,T), RS1000153266 (19:4542935 C>G,T), RS1000345721 (19:4542673 C>A,T), RS1000413661 (19:4557034 T>C), RS1000567055 (19:4552792 G>A,T), RS1000684481 (19:4543706 G>A), RS1000923239 (19:4543894 G>A,C,T), RS1001049327 (19:4553005 T>A,C), RS1001074682 (19:4559093 C>A,T), RS1001081873 (19:4552773 C>G), RS1001442442 (19:4561390 G>A), RS1001684935 (19:4558570 CCTT>C), RS1001743135 (19:4556453 T>C), RS1002078568 (19:4557834 C>G)

Disease associations

OMIM: gene MIM:608873 | disease phenotypes: MIM:618876, MIM:616421, MIM:213000

GenCC curated gene-disease

Disease	Classification	Inheritance
epilepsy, progressive myoclonic, 11	Strong	Autosomal dominant
intellectual disability	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
progressive myoclonus epilepsy	Definitive	AD

Mondo (7): epilepsy, progressive myoclonic, 11 (MONDO:0030034), epilepsy with myoclonic atonic seizures (MONDO:0014633), intellectual disability (MONDO:0001071), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), isolated unilateral hemispheric cerebellar hypoplasia (MONDO:0017112)

Orphanet (6): Epilepsy with myoclonic-atonic seizures (Orphanet:1942), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), Isolated unilateral hemispheric cerebellar hypoplasia (Orphanet:269218), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

17 total (18 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001312	Giant somatosensory evoked potentials
HP:0001320	Cerebellar vermis hypoplasia
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0002063	Rigidity
HP:0002080	Intention tremor
HP:0002376	Developmental regression
HP:0002725	Systemic lupus erythematosus
HP:0010864	Severe intellectual disability
HP:0025352	Typically de novo
HP:0031936	Delayed ability to walk
HP:0000556	Retinal dystrophy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_1987	Metabolite levels	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005058	tyrosine measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
C562568	Cerebellar Hypoplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
(+)-JQ1 compound	decreases expression	3
Benzo(a)pyrene	affects reaction, increases expression, affects methylation, decreases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
nickel sulfate	increases expression	1
pentanal	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
ICG 001	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	affects methylation	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Troglitazone	decreases expression, increases reaction	1
Alitretinoin	decreases expression, increases reaction	1
Air Pollutants	decreases expression, increases abundance	1
Amiodarone	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression	1
Estradiol	decreases expression, affects cotreatment	1
Lead	affects expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Niclosamide	increases expression	1
Phthalic Acids	increases methylation	1

Clinical trials (associated diseases)

198 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)
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
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders