SEPHS1

Summary

SEPHS1 (selenophosphate synthetase 1, HGNC:19685) is a protein-coding gene on chromosome 10p13, encoding Zincore component SEPHS1 (P49903). Core component of the zincore complex, a heterotetramer that acts as a molecular ‘grip’ to stabilize transcription factors at DNA-binding sites across the genome, thereby controlling gene expression. It is a selective cancer dependency (DepMap: 13.9% of cell lines).

This gene encodes an enzyme that synthesizes selenophosphate from selenide and ATP. Selenophosphate is the selenium donor used to synthesize selenocysteine, which is co-translationally incorporated into selenoproteins at in-frame UGA codons.

Source: NCBI Gene 22929 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 65 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 29
• Cancer dependency (DepMap): dependent in 13.9% of screened cell lines
• MANE Select transcript: NM_012247

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19685
Approved symbol	SEPHS1
Name	selenophosphate synthetase 1
Location	10p13
Locus type	gene with protein product
Status	Approved
Aliases	SPS, SPS1
Ensembl gene	ENSG00000086475
Ensembl biotype	protein_coding
OMIM	600902
Entrez	22929

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 17 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000327347, ENST00000378614, ENST00000413411, ENST00000425947, ENST00000494329, ENST00000545675, ENST00000877591, ENST00000877592, ENST00000925347, ENST00000925348, ENST00000925349, ENST00000925350, ENST00000925351, ENST00000925352, ENST00000925353, ENST00000925354, ENST00000925355, ENST00000948205

RefSeq mRNA: 4 — MANE Select: NM_012247 NM_001195602, NM_001195604, NM_001375769, NM_012247

CCDS: CCDS55702, CCDS55703, CCDS7098

Canonical transcript exons

ENST00000327347 — 9 exons

Exon	Start	End
ENSE00000691366	13329698	13329788
ENSE00000691370	13333817	13333971
ENSE00000837388	13328351	13328450
ENSE00000999791	13322835	13323047
ENSE00000999793	13336243	13336350
ENSE00001155849	13348000	13348293
ENSE00001166140	13344758	13345028
ENSE00001478124	13317428	13319356
ENSE00003625156	13338705	13338808

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 98.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.5370 / max 365.7081, expressed in 1770 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
108302	4.8008	1218
108304	3.3463	1366
108299	2.8377	1444
108301	1.4891	752
108303	1.4385	718
108300	0.5123	292
108305	0.1123	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.06	gold quality
ganglionic eminence	UBERON:0004023	97.08	gold quality
embryo	UBERON:0000922	95.27	gold quality
islet of Langerhans	UBERON:0000006	94.27	gold quality
buccal mucosa cell	CL:0002336	93.65	gold quality
adrenal tissue	UBERON:0018303	93.28	gold quality
oocyte	CL:0000023	92.89	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.65	gold quality
secondary oocyte	CL:0000655	92.56	gold quality
rectum	UBERON:0001052	92.25	gold quality
medial globus pallidus	UBERON:0002477	91.76	gold quality
right lobe of liver	UBERON:0001114	91.69	gold quality
left lobe of thyroid gland	UBERON:0001120	91.64	gold quality
endothelial cell	CL:0000115	91.63	gold quality
pancreas	UBERON:0001264	91.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.53	gold quality
thyroid gland	UBERON:0002046	91.50	gold quality
body of pancreas	UBERON:0001150	91.33	gold quality
right lobe of thyroid gland	UBERON:0001119	91.31	gold quality
left adrenal gland	UBERON:0001234	91.27	gold quality
left adrenal gland cortex	UBERON:0035825	91.19	gold quality
mucosa of stomach	UBERON:0001199	91.16	gold quality
right adrenal gland	UBERON:0001233	91.14	gold quality
calcaneal tendon	UBERON:0003701	91.13	gold quality
tendon	UBERON:0000043	90.92	gold quality
right adrenal gland cortex	UBERON:0035827	90.91	gold quality
adrenal gland	UBERON:0002369	90.78	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.65	gold quality
gastrocnemius	UBERON:0001388	90.48	gold quality
muscle of leg	UBERON:0001383	90.45	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	794.03
E-MTAB-7008	no	608.08
E-MTAB-4850	no	271.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

108 targeting SEPHS1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6835-3P	99.93	70.49	2904

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 13.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• the Sps1-encoded enzyme depends on a selenium salvage system that recycles l-selenocysteine, whereas the Sps2 enzyme can function with a selenite assimilation system (PMID:15534230)
• Sps1 affect cell viability upon ionizing radiation via modulation of p53 activity. Sps1 and its product selenophosphate might be involved in cancer prevention in a p53-dependent manner and could be applied to development of a novel cancer therapy. (PMID:16786570)
• Five alternative splice variants of human SPS1 (major type, DeltaE2, DeltaE8, +E9, +E9a) were identified wherein +E9 and +E9a make the same protein. (PMID:20471958)
• Three SNPs in SEPSECS and SEPHS1 were found to significantly interact with serum selenium level and Crohn’s Disease. (PMID:23112913)
• Data confirm interactions among components of the early steps of the selenocysteine biosynthesis pathway (SEPSECS, SECP43, SEPHS1, and SEPHS2); SECP43, which interacts with SEPSECS and SEPHS1, is a globular protein that forms oligomers in vivo. (PMID:28414460)
• SEPHS1 expression is high in undifferentiated embryonic stem cells.SEPHS1 expression is required to obtain pluripotency.SEPHS1 plays a role in the embryonic stem cell survival via reactive oxygen species signaling and apoptosis. (PMID:31607477)
• Selenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis. (PMID:35140209)
• De novo missense variants in exon 9 of SEPHS1 cause a neurodevelopmental condition with developmental delay, poor growth, hypotonia, and dysmorphic features. (PMID:38531365)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sephs1	ENSDARG00000058292
mus_musculus	Sephs1	ENSMUSG00000026662
rattus_norvegicus	Sephs1	ENSRNOG00000018125
drosophila_melanogaster	Sps2	FBGN0032224
drosophila_melanogaster	Sps1	FBGN0261270
caenorhabditis_elegans		WBGENE00012867

Paralogs (1): SEPHS2 (ENSG00000179918)

Protein

Protein identifiers

Zincore component SEPHS1 — P49903 (reviewed: P49903)

Alternative names: Selenide, water dikinase 1, Selenium donor protein 1, Selenophosphate synthase 1

All UniProt accessions (3): P49903, Q5T5U6, Q5T5U7

UniProt curated annotations — full annotation on UniProt →

Function. Core component of the zincore complex, a heterotetramer that acts as a molecular ‘grip’ to stabilize transcription factors at DNA-binding sites across the genome, thereby controlling gene expression. The zincore complex binds specifically to zinc finger transcription factors, such as ZFP91, ZNF652, ZNF526 and PRDM15, and stabilizes them onto their cognate DNA motif. Within the complex, SEPHS1, recognizes and binds the backbone of zinc fingers of transcription factors in a sequence-independent manner via its arginine clamp, enhancing their DNA-binding stability. Plays an essential role in redox homeostasis. May also be involved in selenocysteine biosynthesis by catalyzing formation of selenophosphate from selenide and ATP. Its role in selenocysteine biosynthesis is however unclear and several studies suggest that it does not act as a selenophosphate synthase in vivo or plays an non-essential role. Required for cardiac differentiation.

Subunit / interactions. Homodimer. Component of the zincore complex, a heterotetramer composed of a dimer of QRICH1 and SEPHS1. Component of a complex composed of SEPHS1, SEPHS2, SEPSECS and TRNAU1AP. Homodimer. Heterodimer with isoform 3. Homodimer. Heterodimer with isoform 4. Homodimer. Heterodimer with isoform 1. Homodimer. Heterodimer with isoform 2.

Subcellular location. Nucleus. Chromosome. Cytoplasm Cell membrane. Nucleus membrane Cytoplasm Cytoplasm Cytoplasm.

Tissue specificity. Gradually expressed during the cell cycle until G2/M phase and then decreases. Gradually expressed during the cell cycle until G2/M phase and then decreases. Gradually expressed during the cell cycle until S phase and then decreases.

Disease relevance. Ververi-Brady syndrome 2 (VERBRAS2) [MIM:621325] An autosomal dominant neurodevelopmental disorder characterized by developmental delay, mildly impaired intellectual development, poor growth, hypotonia, and dysmorphic facial features. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by phosphate ions and by potassium ions.

Cofactor. Binds 1 Mg(2+) ion per monomer.

Domain organisation. The arginine clamp secure zinc finger transcription factors to DNA by constraining its zinc fingers in their DNA-bound conformation.

Similarity. Belongs to the selenophosphate synthase 1 family. Class II subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
P49903-1	1, Major type, MT	yes
P49903-2	2, Delta E8
P49903-3	3, Delta E2
P49903-4	4, E9, E9a

RefSeq proteins (4): NP_001182531, NP_001182533, NP_001362698, NP_036379* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004536	SPS/SelD	Family
IPR010918	PurM-like_C_dom	Domain
IPR016188	PurM-like_N	Domain
IPR036676	PurM-like_C_sf	Homologous_superfamily
IPR036921	PurM-like_N_sf	Homologous_superfamily

Pfam: PF00586, PF02769

Enzyme classification (BRENDA):

• EC 2.7.9.3 — selenide, water dikinase (BRENDA: 41 organisms, 55 substrates, 16 inhibitors, 18 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.026–10.3	14
SELENIDE	0.02–0.046	3

Catalyzed reactions (Rhea), 1 shown:

• hydrogenselenide + ATP + H2O = selenophosphate + AMP + phosphate + 2 H(+) (RHEA:18737)

UniProt features (58 total): helix 14, strand 11, mutagenesis site 9, binding site 8, sequence variant 4, site 3, splice variant 3, initiator methionine 1, chain 1, modified residue 1, active site 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3FD5	X-RAY DIFFRACTION	1.9
3FD6	X-RAY DIFFRACTION	1.95
9HJU	ELECTRON MICROSCOPY	3.16
9HJT	ELECTRON MICROSCOPY	3.26

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49903-F1	89.76	0.79

Functional residue map

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

Catalytic / active sites (4): 32 (important for catalytic activity); 330 (arginine clamp); 371 (arginine clamp); 31

Ligand- & substrate-binding residues (8): 265; 32 (in other chain); 67–69 (in other chain); 69; 87 (in other chain); 110 (in other chain); 110; 161–164

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (9):

Position	Phenotype
85	strongly reduced adp hydrolysis.
226	slightly decreased dna-binding and transcriptional activity of zfp91.
268	no change in atp-binding.
270	no change in atp-binding.
273	loss of atp-binding.
274	reduced atp-binding.
274	increased atp-binding.
330	decreased dna-binding and transcriptional activity of zfp91.
369	slightly decreased dna-binding and transcriptional activity of zfp91.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 221 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, HORIUCHI_WTAP_TARGETS_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, MATTIOLI_MGUS_VS_PCL, GOBP_SERINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, PUJANA_CHEK2_PCC_NETWORK, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, MUELLER_PLURINET, chr10p13, SOX9_B1, MODULE_195, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP

GO Biological Process (3): L-selenocysteine biosynthetic process (GO:0016260), protein modification process (GO:0036211), cell redox homeostasis (GO:0045454)

GO Molecular Function (11): selenide, water dikinase activity (GO:0004756), ATP binding (GO:0005524), GTP binding (GO:0005525), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), protein heterodimerization activity (GO:0046982), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): cytoplasm (GO:0005737), plasma membrane (GO:0005886), nuclear membrane (GO:0031965), nucleus (GO:0005634), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
purine ribonucleoside triphosphate binding	2
protein dimerization activity	2
cellular anatomical structure	2
modified amino acid biosynthetic process	1
L-amino acid biosynthetic process	1
proteinogenic amino acid biosynthetic process	1
protein metabolic process	1
macromolecule modification	1
cellular homeostasis	1
kinase activity	1
phosphotransferase activity, paired acceptors	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide binding	1
protein binding	1
identical protein binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
nucleus	1
nuclear envelope	1
organelle membrane	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1024 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEPHS1	EEFSEC	P57772	931
SEPHS1	SEPSECS	Q9HD40	893
SEPHS1	DIO1	P49895	822
SEPHS1	PSTK	Q8IV42	807
SEPHS1	SARS1	P49591	721
SEPHS1	M0R2C6	M0R2C6	693
SEPHS1	SARS2	Q9NP81	693
SEPHS1	TRNAU1AP	Q9NX07	689
SEPHS1	SECISBP2	Q96T21	686
SEPHS1	SELENOT	P62341	676
SEPHS1	SCLY	Q96I15	634
SEPHS1	SELENOK	Q9Y6D0	600
SEPHS1	SELENOO	Q9BVL4	589
SEPHS1	SELENOV	P59797	571
SEPHS1	SELENOF	O60613	569

IntAct

76 interactions, top by confidence:

A	B	Type	Score
SEPHS1	SEPHS1	psi-mi:“MI:0915”(physical association)	0.800
ZBTB25	SEPHS1	psi-mi:“MI:0915”(physical association)	0.780
QRICH1	SEPHS1	psi-mi:“MI:0915”(physical association)	0.780
SEPHS1	QRICH1	psi-mi:“MI:0915”(physical association)	0.780
SEPHS1	QRICH1	psi-mi:“MI:0914”(association)	0.780
SEPHS1	ZNF526	psi-mi:“MI:0915”(physical association)	0.560
ZNF202	SEPHS1	psi-mi:“MI:0915”(physical association)	0.560
SEPHS1	PLAGL2	psi-mi:“MI:0915”(physical association)	0.560
SEPHS1	ZNF276	psi-mi:“MI:0915”(physical association)	0.560
SEPHS1	ZNF474	psi-mi:“MI:0915”(physical association)	0.560
SEPHS1	XAF1	psi-mi:“MI:0915”(physical association)	0.560
ISX	MOCS3	psi-mi:“MI:0914”(association)	0.530
SEPHS1	SEPHS2	psi-mi:“MI:0915”(physical association)	0.500
SEPHS1	CDCA4	psi-mi:“MI:0915”(physical association)	0.370
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
HLX	SCAF4	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
rep	TAF4	psi-mi:“MI:0914”(association)	0.350

BioGRID (102): SEPHS1 (Two-hybrid), SEPHS1 (Two-hybrid), QRICH1 (Two-hybrid), SEPHS1 (Affinity Capture-MS), SEPHS1 (Affinity Capture-MS), SEPHS1 (Affinity Capture-MS), SEPHS1 (Two-hybrid), ACADS (Co-fractionation), CRKL (Co-fractionation), DDX19A (Co-fractionation), G6PD (Co-fractionation), HSPB1 (Co-fractionation), MCFD2 (Co-fractionation), PDCD6 (Co-fractionation), PFAS (Co-fractionation)

ESM2 similar proteins: A1YIZ1, A2ARP1, A7Z050, B5DFG1, E1BPN0, E7FCP8, O14976, O18373, O35385, P0C644, P33402, P46489, P49903, P57075, P97364, P97874, Q05145, Q0VC82, Q38A34, Q3V3E1, Q42713, Q43307, Q4Q0M0, Q5R4H0, Q5RDF1, Q5RF87, Q66I14, Q6ESZ9, Q6GL12, Q6PF47, Q6PFW1, Q7Z3D6, Q7ZW38, Q80V31, Q84MA1, Q8BGG7, Q8BH69, Q8BH86, Q8C0D5, Q8H1E2

Diamond homologs: A0KKE7, A0KRK1, A1APP9, A1RP94, A1VE87, A1YIZ1, A3DA84, A3MZ45, A4SMM1, A4W9I2, A4YBB9, A5UG02, A6QBB7, A6WHQ5, A7MNU8, A7ZMN3, A8A0V7, A8EUZ4, A8MHJ6, A9KPW1, A9KW79, B1K568, B1Z181, B2RLG7, B2TKP6, B2V0F0, B3E7F7, B4EJQ7, B5EBG1, B8DNL1, B8EBM9, B8ES21, B8FWU2, C4ZDB0, C6E5Z5, O18373, O62461, O67139, P16456, P43911

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	39
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1343383	NM_012247.5(SEPHS1):c.1111C>T (p.Arg371Trp)	Pathogenic
1343386	NM_012247.5(SEPHS1):c.1054T>G (p.Trp352Gly)	Pathogenic
1343384	NM_012247.5(SEPHS1):c.1111C>G (p.Arg371Gly)	Likely pathogenic

SpliceAI

1838 predictions. Top by Δscore:

Variant	Effect	Δscore
10:13319354:CGC:C	acceptor_gain	1.0000
10:13319355:GCC:G	acceptor_loss	1.0000
10:13328346:CATA:C	donor_loss	1.0000
10:13328349:ACC:A	donor_loss	1.0000
10:13328447:CAGG:C	acceptor_gain	1.0000
10:13328448:AGG:A	acceptor_gain	1.0000
10:13328448:AGGCT:A	acceptor_loss	1.0000
10:13328449:GG:G	acceptor_gain	1.0000
10:13328451:C:CC	acceptor_gain	1.0000
10:13328451:CT:C	acceptor_loss	1.0000
10:13328452:T:C	acceptor_loss	1.0000
10:13328457:A:AC	acceptor_gain	1.0000
10:13328457:A:C	acceptor_gain	1.0000
10:13328463:A:AC	acceptor_gain	1.0000
10:13328463:A:C	acceptor_gain	1.0000
10:13328465:G:C	acceptor_gain	1.0000
10:13328465:G:GC	acceptor_gain	1.0000
10:13328469:G:C	acceptor_gain	1.0000
10:13328469:G:GC	acceptor_gain	1.0000
10:13329696:A:AC	donor_gain	1.0000
10:13329697:C:CC	donor_gain	1.0000
10:13329697:CG:C	donor_gain	1.0000
10:13329784:CTGGC:C	acceptor_gain	1.0000
10:13329785:TGGC:T	acceptor_gain	1.0000
10:13329789:C:CC	acceptor_gain	1.0000
10:13329789:C:CG	acceptor_loss	1.0000
10:13333810:AACTT:A	donor_loss	1.0000
10:13333811:ACTTA:A	donor_loss	1.0000
10:13333812:CTT:C	donor_loss	1.0000
10:13333813:TTA:T	donor_loss	1.0000

AlphaMissense

2594 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:13319230:G:T	A364D	1.000
10:13319257:C:A	G355V	1.000
10:13319257:C:T	G355E	1.000
10:13319258:C:A	G355W	1.000
10:13319258:C:G	G355R	1.000
10:13319258:C:T	G355R	1.000
10:13319263:A:C	I353S	1.000
10:13319263:A:G	I353T	1.000
10:13319263:A:T	I353N	1.000
10:13319267:A:G	W352R	1.000
10:13319267:A:T	W352R	1.000
10:13319314:A:G	F336S	1.000
10:13319340:A:C	C327W	1.000
10:13319342:A:G	C327R	1.000
10:13319347:A:G	L325P	1.000
10:13322855:C:T	G315E	1.000
10:13322856:C:A	G315W	1.000
10:13322918:G:T	P294Q	1.000
10:13322919:G:A	P294S	1.000
10:13322921:A:G	L293P	1.000
10:13322930:A:T	I290N	1.000
10:13322936:A:G	F288S	1.000
10:13322966:A:G	L278P	1.000
10:13322990:C:T	G270E	1.000
10:13323011:G:T	A263D	1.000
10:13323020:G:T	A260D	1.000
10:13329738:C:A	G204V	1.000
10:13329738:C:T	G204E	1.000
10:13329739:C:A	G204W	1.000
10:13329739:C:G	G204R	1.000

dbSNP variants (sampled 300 via entrez): RS1000055556 (10:13322085 G>A,C), RS1000130285 (10:13329605 A>G), RS1000145574 (10:13338161 G>A), RS1000281568 (10:13324089 C>A,G), RS1000352831 (10:13343757 T>C), RS1000477457 (10:13339616 C>T), RS1000503974 (10:13324270 T>C), RS1000509986 (10:13339976 A>G), RS1000561473 (10:13348400 A>G), RS1000681209 (10:13344522 TTAAAAAAAAA>T), RS1000733022 (10:13344308 A>C), RS1000925336 (10:13333535 G>T), RS1001010583 (10:13324253 G>A,T), RS1001086504 (10:13345303 T>C), RS1001124766 (10:13334254 T>G)

Disease associations

OMIM: gene MIM:600902 | disease phenotypes: MIM:621325

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (2): Ververi-Brady syndrome 2 (MONDO:0980726), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000193	Bifid uvula
HP:0000233	Thin vermilion border
HP:0000288	Abnormality of the philtrum
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000391	Thickened helices
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000490	Deeply set eye
HP:0000508	Ptosis
HP:0000527	Long eyelashes
HP:0000574	Thick eyebrow
HP:0000621	Entropion
HP:0000687	Widely spaced teeth
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001324	Muscle weakness
HP:0002553	Highly arched eyebrow
HP:0004467	Preauricular pit
HP:0008559	Hypoplastic superior helix
HP:0008897	Postnatal growth retardation
HP:0009765	Low hanging columella
HP:0010296	Ankyloglossia
HP:0011968	Feeding difficulties
HP:0012443	Abnormal brain morphology
HP:0100015	Stahl ear

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004250_22	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	2.000000e-06
GCST009391_681	Metabolite levels	9.000000e-06
GCST012310_17	Schizophrenia x sex interaction	6.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007965	response to combination chemotherapy
EFO:0010506	kynurenic acid measurement
EFO:0008343	sex interaction measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	7
bisphenol A	affects cotreatment, decreases methylation, decreases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	3
cobaltous chloride	decreases expression	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Tretinoin	decreases expression, increases expression	2
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
phenethyl isothiocyanate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	decreases expression, affects cotreatment	1
NSC 689534	affects binding, decreases expression	1
Decitabine	affects expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3GS	Abcam HEK293T SEPHS1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice