SEPSECS

Summary

SEPSECS (Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase, HGNC:30605) is a protein-coding gene on chromosome 4p15.2, encoding O-phosphoseryl-tRNA(Sec) selenium transferase (Q9HD40). Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis. It is a selective cancer dependency (DepMap: 54.4% of cell lines).

The amino acid selenocysteine is the only amino acid that does not have its own tRNA synthetase. Instead, this amino acid is synthesized on its cognate tRNA in a three step process. The protein encoded by this gene catalyzes the third step in the process, the conversion of O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec).

Source: NCBI Gene 51091 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pontocerebellar hypoplasia type 2D (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 801 total — 48 pathogenic, 47 likely-pathogenic
• Phenotypes (HPO): 56
• Cancer dependency (DepMap): dependent in 54.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_016955

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30605
Approved symbol	SEPSECS
Name	Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase
Location	4p15.2
Locus type	gene with protein product
Status	Approved
Aliases	SLA/LP, SLA, SLA-p35, SecS
Ensembl gene	ENSG00000109618
Ensembl biotype	protein_coding
OMIM	613009
Entrez	51091

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 8 retained_intron, 5 protein_coding, 4 nonsense_mediated_decay

ENST00000358971, ENST00000382103, ENST00000503150, ENST00000505513, ENST00000514585, ENST00000515272, ENST00000680581, ENST00000680824, ENST00000681071, ENST00000681166, ENST00000681341, ENST00000681374, ENST00000681640, ENST00000681948, ENST00000853997, ENST00000853998, ENST00000952587

RefSeq mRNA: 2 — MANE Select: NM_016955 NM_001410714, NM_016955

CCDS: CCDS3432, CCDS93487

Canonical transcript exons

ENST00000382103 — 11 exons

Exon	Start	End
ENSE00001490927	25120014	25124225
ENSE00002264526	25160256	25160449
ENSE00003484580	25151960	25152062
ENSE00003503189	25156856	25156974
ENSE00003505475	25154998	25155151
ENSE00003519320	25145004	25145133
ENSE00003530654	25125694	25125784
ENSE00003590416	25158953	25159107
ENSE00003620511	25156037	25156195
ENSE00003621173	25127264	25127357
ENSE00003656136	25144774	25144865

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 89.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.8080 / max 85.6525, expressed in 1737 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51681	7.6562	1714
51682	0.8679	512
51683	0.2839	147

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	89.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.88	gold quality
right lobe of liver	UBERON:0001114	87.39	gold quality
jejunal mucosa	UBERON:0000399	86.30	gold quality
liver	UBERON:0002107	86.11	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.58	gold quality
calcaneal tendon	UBERON:0003701	85.44	gold quality
tendon	UBERON:0000043	83.78	gold quality
kidney epithelium	UBERON:0004819	83.68	silver quality
body of pancreas	UBERON:0001150	82.68	gold quality
epithelial cell of pancreas	CL:0000083	82.58	silver quality
rectum	UBERON:0001052	81.55	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.28	gold quality
mucosa of stomach	UBERON:0001199	80.54	gold quality
small intestine	UBERON:0002108	80.22	gold quality
pancreas	UBERON:0001264	80.19	gold quality
duodenum	UBERON:0002114	80.19	gold quality
sperm	CL:0000019	79.81	gold quality
monocyte	CL:0000576	79.30	gold quality
metanephros cortex	UBERON:0010533	79.24	gold quality
transverse colon	UBERON:0001157	79.21	gold quality
leukocyte	CL:0000738	79.02	gold quality
tendon of biceps brachii	UBERON:0008188	78.75	gold quality
gall bladder	UBERON:0002110	78.58	gold quality
ventricular zone	UBERON:0003053	78.55	gold quality
oviduct epithelium	UBERON:0004804	78.40	gold quality
right ovary	UBERON:0002118	78.32	gold quality
left ovary	UBERON:0002119	78.31	gold quality
pancreatic ductal cell	CL:0002079	78.26	silver quality
skin of abdomen	UBERON:0001416	78.21	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	5.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

188 targeting SEPSECS, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
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-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 54.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 14)

• crystal structure of tRNA(Sec) in complex with SepSecS, phosphoserine, and thiophosphate, together with in vivo and in vitro enzyme assays, supports a pyridoxal phosphate-dependent mechanism of Sec-tRNA(Sec) formation (PMID:19608919)
• detectable in liver extracts of autoimmune hepatitis patients’ cells as the major autoantigenic component (PMID:19683415)
• The human SepSecS protein is also known as soluble liver antigen/liver pancreas (SLA/LP), which represents one of the antigens of autoimmune hepatitis. (PMID:20623998)
• SepSecS mutations cause autosomal-recessive progressive cerebellocerebral atrophy in Jews of Iraqi and Moroccan ancestry. (PMID:20920667)
• Three SNPs in SEPSECS and SEPHS1 were found to significantly interact with serum selenium level and Crohn’s Disease. (PMID:23112913)
• Data suggest SEPSECS silencing in placental trophoblasts inhibits proliferation, induces apoptosis, and reduces production of progesterone/chorionic gonadotropin (P/hCG); SEPSECS over-expression promotes cell proliferation and secretion of P/hCG. (PMID:23966103)
• structural analysis of the terminal catalytic complex in selenocysteine synthesis (PMID:25190812)
• results suggest SEPSECS as a candidate gene for progressive encephalopathies with lactate elevation. (PMID:26115735)
• The progression of clinical symptoms in these families is evidently slower than in previously reported cases, and the cerebellar atrophy milder by brain MRI, indicating that SEPSECS mutations are also involved in milder late-onset cerebellar atrophy. (PMID:26888482)
• Structural basis for early-onset neurological disorders caused by mutations in human selenocysteine synthase has been described. (PMID:27576344)
• Epileptic encephalopathy with burst suppression without brain malformations is associated with pathogenic variation in SEPSECS. (PMID:28133863)
• Human Genetic Disorders Resulting in Systemic Selenoprotein Deficiency. (PMID:34884733)
• Biallelic SEPSECS variants in two siblings with pontocerebellar hypoplasia type 2D underscore the relevance of splice-disrupting synonymous variants in disease. (PMID:35091508)
• Integrative Analysis Unveils the Correlation of Aminoacyl-tRNA Biosynthesis Metabolites with the Methylation of the SEPSECS Gene in Huntington’s Disease Brain Tissue. (PMID:37761892)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sepsecs	ENSDARG00000033861
mus_musculus	Sepsecs	ENSMUSG00000029173
rattus_norvegicus	Sepsecs	ENSRNOG00000049244
drosophila_melanogaster	SecS	FBGN0037347
caenorhabditis_elegans		WBGENE00008379

Protein

Protein identifiers

O-phosphoseryl-tRNA(Sec) selenium transferase — Q9HD40 (reviewed: Q9HD40)

Alternative names: Liver-pancreas antigen, SLA-p35, SLA/LP autoantigen, Selenocysteine synthase, Selenocysteinyl-tRNA(Sec) synthase, Sep-tRNA:Sec-tRNA synthase, Soluble liver antigen, UGA suppressor tRNA-associated protein, tRNA(Ser/Sec)-associated antigenic protein

All UniProt accessions (5): Q9HD40, A0A7P0TA23, A0A7P0Z4P3, H0Y9D2, J3KP25

UniProt curated annotations — full annotation on UniProt →

Function. Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.

Subunit / interactions. Homotetramer formed by a catalytic dimer and a non-catalytic dimer serving as a binding platform that orients tRNASec for catalysis. Each tetramer binds the CCA ends of two tRNAs which point to the active sites of the catalytic dimer. Component of a complex composed of SEPHS1, SEPHS2, SEPSECS and TRNAU1AP.

Subcellular location. Cytoplasm.

Tissue specificity. Primarily expressed in liver, pancreas, kidney and lung. Overexpressed in PHA-stimulated T-cells.

Disease relevance. Pontocerebellar hypoplasia 2D (PCH2D) [MIM:613811] A disorder characterized by postnatal onset of progressive atrophy of the cerebrum and cerebellum, microcephaly, profound intellectual disability, spasticity, and variable seizures. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Aminoacyl-tRNA biosynthesis; selenocysteinyl-tRNA(Sec) biosynthesis; selenocysteinyl-tRNA(Sec) from L-seryl-tRNA(Sec) (archaeal/eukaryal route): step 2/2.

Miscellaneous. Possible diagnostic marker for autoimmune hepatitis (AIH). May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the SepSecS family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9HD40-1	1	yes
Q9HD40-2	2
Q9HD40-3	3

RefSeq proteins (2): NP_001397643, NP_058651* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008829	SepSecS/SepCysS	Family
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily
IPR019793	Peroxidases_heam-ligand_BS	Binding_site
IPR019872	Sec-tRNA_Se_transferase	Family

Pfam: PF05889

Enzyme classification (BRENDA):

• EC 2.9.1.2 — O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase (BRENDA: 8 organisms, 13 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• O-phospho-L-seryl-tRNA(Sec) + selenophosphate + H2O = L-selenocysteinyl-tRNA(Sec) + 2 phosphate (RHEA:25041)

UniProt features (72 total): helix 17, strand 17, binding site 8, mutagenesis site 8, sequence conflict 5, turn 4, region of interest 3, splice variant 3, sequence variant 3, modified residue 2, chain 1, site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8G9Z	X-RAY DIFFRACTION	2.07
7L1T	X-RAY DIFFRACTION	2.25
4ZDL	X-RAY DIFFRACTION	2.26
7MDL	X-RAY DIFFRACTION	2.32
4ZDO	X-RAY DIFFRACTION	2.65
4ZDP	X-RAY DIFFRACTION	2.7
3HL2	X-RAY DIFFRACTION	2.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HD40-F1	92.63	0.88

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 (1): 74 (may act as a substrate filter by repelling compounds with a negatively charged alpha-carboxylate)

Ligand- & substrate-binding residues (8): 398; 463; 75; 97; 98; 105; 271; 313

Post-translational modifications (2): 14, 284

Mutagenesis-validated functional residues (8):

Position	Phenotype
75	inactive in vivo.
97	indistinguishable from wild-type.
105	inactive in vivo.
173	indistinguishable from wild-type.
284	loss of activity.
313	inactive in vivo.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2408557	Selenocysteine synthesis
R-HSA-1430728	Metabolism
R-HSA-2408522	Selenoamino acid metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 551 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, MCLACHLAN_DENTAL_CARIES_UP, LU_IL4_SIGNALING, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, RORA1_01, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, MODULE_45, MODULE_64, GOBP_TRNA_METABOLIC_PROCESS, GOBP_SERINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, MODULE_16, SHIPP_DLBCL_CURED_VS_FATAL_DN, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS

GO Biological Process (3): selenocysteine incorporation (GO:0001514), conversion of seryl-tRNAsec to selenocys-tRNAsec (GO:0001717), translation (GO:0006412)

GO Molecular Function (6): tRNA binding (GO:0000049), O-phosphoseryl-tRNA(Sec) selenium transferase activity (GO:0098621), RNA binding (GO:0003723), protein binding (GO:0005515), transferase activity (GO:0016740), selenotransferase activity (GO:0016785)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Selenoamino acid metabolism	1
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
translational readthrough	1
charged-tRNA amino acid modification	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
RNA binding	1
selenotransferase activity	1
catalytic activity, acting on a tRNA	1
nucleic acid binding	1
binding	1
catalytic activity	1
transferase activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1704 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEPSECS	PSTK	Q8IV42	993
SEPSECS	SARS1	P49591	965
SEPSECS	M0R2C6	M0R2C6	960
SEPSECS	SARS2	Q9NP81	960
SEPSECS	TRNAU1AP	Q9NX07	925
SEPSECS	EEFSEC	P57772	912
SEPSECS	SEPHS2	Q99611	902
SEPSECS	SEPHS1	P49903	893
SEPSECS	DNAL1	Q4LDG9	874
SEPSECS	SECISBP2	Q96T21	867
SEPSECS	KANK1	Q14678	768
SEPSECS	SCLY	Q96I15	716
SEPSECS	TSEN34	Q9BSV6	703
SEPSECS	AP4M1	O00189	697
SEPSECS	NUP210	Q8TEM1	696

IntAct

24 interactions, top by confidence:

A	B	Type	Score
YBX1	HNRNPR	psi-mi:“MI:0915”(physical association)	0.770
rep	MPHOSPH10	psi-mi:“MI:0914”(association)	0.660
gag	SEPSECS	psi-mi:“MI:0914”(association)	0.560
gag	EEF1E1	psi-mi:“MI:0914”(association)	0.560
SEPSECS	gag	psi-mi:“MI:0915”(physical association)	0.560
gag	SEPSECS	psi-mi:“MI:0915”(physical association)	0.560
LZTFL1	BUB3	psi-mi:“MI:0914”(association)	0.510
gag	SDCBP	psi-mi:“MI:0914”(association)	0.460
RBPJ	RPA2	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
TNFAIP3	FZD7	psi-mi:“MI:0914”(association)	0.350
SOX2	CBX4	psi-mi:“MI:0914”(association)	0.350
RNASEL	UNC119B	psi-mi:“MI:0914”(association)	0.350
COP1	SPOP	psi-mi:“MI:0914”(association)	0.350
ABLIM1	NMT1	psi-mi:“MI:0914”(association)	0.350
BCAS2	ISY1-RAB43	psi-mi:“MI:0914”(association)	0.350
CST8	VGF	psi-mi:“MI:0914”(association)	0.350
HEXIM1	POLRMT	psi-mi:“MI:0914”(association)	0.350
gag	EIF2AK2	psi-mi:“MI:0914”(association)	0.350
gag	gag	psi-mi:“MI:0914”(association)	0.350
SEPSECS	LZTFL1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (28): SEPSECS (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), LZTFL1 (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), SEPSECS (Affinity Capture-MS), SEPSECS (Two-hybrid)

ESM2 similar proteins: A0JN39, A2XKU9, A4FUD3, A4IHJ3, A7RHL5, A9NK39, B4YYA9, B5X8A5, D2SW95, O00232, O08810, O80526, P23514, P53618, Q01587, Q15029, Q28EN2, Q28EX9, Q2KJ25, Q2KJD7, Q32LQ4, Q3ZBN0, Q42450, Q498C5, Q4KML4, Q5F3X4, Q5FWT7, Q5M8Z0, Q5R4C4, Q5R6E0, Q5R922, Q5RAK7, Q5RBI3, Q5RJU0, Q5XGM3, Q5ZIA5, Q5ZJJ8, Q641F1, Q66HV4, Q6AVK1

Diamond homologs: A0A3S7WQS5, Q18953, Q28EN2, Q54VQ6, Q5RAK7, Q61JN8, Q6P6M7, Q803A7, Q8TXK0, Q9HD40, Q58027, Q6LZM9, O30207

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	48
Likely pathogenic	47
Uncertain significance	244
Likely benign	352
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1298330	NM_016955.4(SEPSECS):c.1A>T (p.Met1Leu)	Pathogenic
1361835	NM_016955.4(SEPSECS):c.154del (p.Glu52fs)	Pathogenic
1413924	NM_016955.4(SEPSECS):c.903del (p.Phe302fs)	Pathogenic
1420995	NM_016955.4(SEPSECS):c.361_362insGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGAGATCGAGACCATCCTGGCTAACACGGTGAAACCCCGTCTCTACNNNNNNNNNNAAAAAAAAAAAAAAAAAAAATTACCAATTCTT (p.Leu121fs)	Pathogenic
1429767	NM_016955.4(SEPSECS):c.908_911del (p.Ile303fs)	Pathogenic
1453126	NM_016955.4(SEPSECS):c.480_481insC (p.Lys161fs)	Pathogenic
1453646	NM_016955.4(SEPSECS):c.631del (p.Glu211fs)	Pathogenic
1454026	NC_000004.11:g.(?25128876)(25128989_?)del	Pathogenic
1459323	NC_000004.11:g.(?25160565)(25162001_?)del	Pathogenic
18400	NM_016955.4(SEPSECS):c.1001A>G (p.Tyr334Cys)	Pathogenic
1974688	NM_016955.4(SEPSECS):c.746_755del (p.His249fs)	Pathogenic
1997873	NM_016955.4(SEPSECS):c.902C>G (p.Ser301Ter)	Pathogenic
2014918	NM_016955.4(SEPSECS):c.267C>G (p.Tyr89Ter)	Pathogenic
2023922	NM_016955.4(SEPSECS):c.651dup (p.Leu218fs)	Pathogenic
2101509	NM_016955.4(SEPSECS):c.961_970del (p.Asp321fs)	Pathogenic
2112762	NM_016955.4(SEPSECS):c.470del (p.His157fs)	Pathogenic
2126237	NM_016955.4(SEPSECS):c.531dup (p.Ser178fs)	Pathogenic
2128802	NM_016955.4(SEPSECS):c.648C>A (p.Cys216Ter)	Pathogenic
2696232	NM_016955.4(SEPSECS):c.235dup (p.Val79fs)	Pathogenic
2710858	NM_003235.5(TG):c.7342C>T (p.Gln2448Ter)	Pathogenic
2720183	NM_016955.4(SEPSECS):c.1058_1061del (p.Lys353fs)	Pathogenic
2726893	NM_016955.4(SEPSECS):c.137G>A (p.Trp46Ter)	Pathogenic
2763928	NM_016955.4(SEPSECS):c.864del (p.Pro289fs)	Pathogenic
2771302	NM_016955.4(SEPSECS):c.1043del (p.Leu348fs)	Pathogenic
2772091	NM_016955.4(SEPSECS):c.234_235del (p.Arg78fs)	Pathogenic
2795923	NM_016955.4(SEPSECS):c.435del (p.Gly145_Met146insTer)	Pathogenic
2818731	NM_016955.4(SEPSECS):c.1429G>T (p.Glu477Ter)	Pathogenic
2823635	NM_016955.4(SEPSECS):c.296del (p.Gly99fs)	Pathogenic
2835225	NM_016955.4(SEPSECS):c.992C>A (p.Ser331Ter)	Pathogenic
2847414	NM_003235.5(TG):c.7277del (p.His2426fs)	Pathogenic

SpliceAI

1517 predictions. Top by Δscore:

Variant	Effect	Δscore
4:25125690:TTA:T	donor_loss	1.0000
4:25125691:TA:T	donor_loss	1.0000
4:25125692:A:AC	donor_gain	1.0000
4:25125692:AC:A	donor_gain	1.0000
4:25125693:C:CG	donor_gain	1.0000
4:25125693:CC:C	donor_gain	1.0000
4:25125693:CCT:C	donor_gain	1.0000
4:25125693:CCTG:C	donor_gain	1.0000
4:25125693:CCTGG:C	donor_gain	1.0000
4:25125780:CATAG:C	acceptor_gain	1.0000
4:25125781:ATAG:A	acceptor_gain	1.0000
4:25125782:TAG:T	acceptor_gain	1.0000
4:25125783:AG:A	acceptor_gain	1.0000
4:25125783:AGCTG:A	acceptor_loss	1.0000
4:25125784:GC:G	acceptor_loss	1.0000
4:25125785:C:CC	acceptor_gain	1.0000
4:25127358:C:A	acceptor_loss	1.0000
4:25127359:T:A	acceptor_loss	1.0000
4:25144767:AGCTT:A	donor_loss	1.0000
4:25144768:GCTTA:G	donor_loss	1.0000
4:25144769:CTTA:C	donor_loss	1.0000
4:25144770:TTAC:T	donor_loss	1.0000
4:25144771:TAC:T	donor_loss	1.0000
4:25144772:A:AG	donor_loss	1.0000
4:25144773:CCTTT:C	donor_gain	1.0000
4:25144862:CTTC:C	acceptor_gain	1.0000
4:25144863:TTC:T	acceptor_gain	1.0000
4:25144866:C:A	acceptor_loss	1.0000
4:25144866:C:CC	acceptor_gain	1.0000
4:25144867:T:A	acceptor_loss	1.0000

AlphaMissense

3280 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:25144862:C:G	R313T	0.999
4:25145087:T:A	K284I	0.999
4:25145090:T:A	D283V	0.999
4:25145095:G:C	S281R	0.999
4:25145095:G:T	S281R	0.999
4:25145097:T:G	S281R	0.999
4:25156143:A:C	S147R	0.999
4:25156143:A:T	S147R	0.999
4:25156145:T:G	S147R	0.999
4:25156929:T:A	Q105H	0.999
4:25156929:T:G	Q105H	0.999
4:25156954:C:G	R97P	0.999
4:25156957:C:T	G96E	0.999
4:25156963:C:T	G94D	0.999
4:25158971:A:T	V84D	0.999
4:25158993:C:A	G77W	0.999
4:25158998:C:A	R75M	0.999
4:25159038:C:G	D62H	0.999
4:25144859:G:T	A314D	0.998
4:25144861:T:A	R313S	0.998
4:25144861:T:G	R313S	0.998
4:25144865:C:T	G312E	0.998
4:25145004:C:G	G312R	0.998
4:25145004:C:T	G312R	0.998
4:25145010:A:C	Y310D	0.998
4:25145083:A:C	N285K	0.998
4:25145083:A:T	N285K	0.998
4:25145090:T:G	D283A	0.998
4:25145102:A:T	V279D	0.998
4:25155018:A:C	F227L	0.998

dbSNP variants (sampled 300 via entrez): RS1000016880 (4:25158615 T>C), RS1000043427 (4:25151640 C>A,T), RS1000264536 (4:25158121 C>G,T), RS1000300244 (4:25141686 T>C), RS1000375427 (4:25127967 G>T), RS1000394081 (4:25128181 C>G), RS1000432102 (4:25134700 T>C), RS10004441 (4:25123293 C>G), RS1000559648 (4:25154493 T>C,G), RS1000650757 (4:25141966 T>A), RS1000651301 (4:25156908 G>A,C), RS1000719321 (4:25158575 T>C), RS1000734759 (4:25147693 G>C), RS1000834718 (4:25122430 T>C), RS1000885580 (4:25122149 G>A)

Disease associations

OMIM: gene MIM:613009 | disease phenotypes: MIM:613811, MIM:274700, MIM:607596, MIM:213000, MIM:617468, MIM:108600, MIM:608175

GenCC curated gene-disease

Disease	Classification	Inheritance
pontocerebellar hypoplasia type 2D	Definitive	Autosomal recessive
progressive cerebello-cerebral atrophy	Supportive	Autosomal recessive
pontocerebellar hypoplasia type 2	Supportive	Autosomal recessive

Mondo (11): pontocerebellar hypoplasia type 2D (MONDO:0013438), thyroid dyshormonogenesis 3 (MONDO:0010135), cerebellar ataxia (MONDO:0000437), neurodegenerative disease (MONDO:0005559), pontocerebellar hypoplasia (MONDO:0020135), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), arthrogryposis multiplex congenita (MONDO:0015168), spastic ataxia (MONDO:0017845), autoimmune thyroid disease, susceptibility to, 3 (MONDO:0011982), (MONDO:0016589), pontocerebellar hypoplasia type 2 (MONDO:0016759)

Orphanet (9): Progressive cerebello-cerebral atrophy (Orphanet:247198), Pontocerebellar hypoplasia type 2 (Orphanet:2524), Familial thyroid dyshormonogenesis (Orphanet:95716), Rare ataxia (Orphanet:102002), Non-syndromic pontocerebellar hypoplasia (Orphanet:98523), Arthrogryposis multiplex congenita (Orphanet:1037), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), Spastic ataxia (Orphanet:316226)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000253	Progressive microcephaly
HP:0000340	Sloping forehead
HP:0000737	Irritability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001320	Cerebellar vermis hypoplasia
HP:0001321	Cerebellar hypoplasia
HP:0001999	Abnormal facial shape
HP:0002020	Gastroesophageal reflux
HP:0002033	Poor suck
HP:0002059	Cerebral atrophy
HP:0002072	Chorea
HP:0002079	Hypoplasia of the corpus callosum
HP:0002104	Apnea
HP:0002119	Ventriculomegaly
HP:0002123	Generalized myoclonic seizure
HP:0002169	Clonus
HP:0002187	Profound intellectual disability
HP:0002268	Paroxysmal dystonia
HP:0002350	Cerebellar cyst
HP:0002360	Sleep disturbance
HP:0002365	Hypoplasia of the brainstem
HP:0002510	Spastic tetraplegia
HP:0002518	Abnormal periventricular white matter morphology
HP:0002536	Abnormal cortical gyration

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001509_12	Vitiligo	2.000000e-08
GCST001531_15	Temperament	5.000000e-06
GCST001984_1	Graves’ disease	8.000000e-09
GCST003995_19	Tonsillectomy	1.000000e-10
GCST004400_1	Bone erosion in rheumatoid arthritis	4.000000e-06
GCST004785_46	Vitiligo	2.000000e-13
GCST005014_65	Tonsillectomy	1.000000e-10
GCST009597_188	Multiple sclerosis	7.000000e-06
GCST010703_219	Brain morphology (MOSTest)	4.000000e-11
GCST90002382_260	Eosinophil percentage of white cells	8.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004825	temperament and character inventory
EFO:0007924	tonsillectomy risk measurement
EFO:0005413	joint damage measurement
EFO:0004346	neuroimaging measurement
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D019636	Neurodegenerative Diseases	C10.574
C562568	Cerebellar Hypoplasia (supp.)
C580383	Pontocerebellar Hypoplasia (supp.)
C548070	Pontocerebellar Hypoplasia Type 2 (supp.)
C564815	Spastic Ataxia (supp.)
C562769	Thyroid Dyshormonogenesis 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression	4
Acetaminophen	decreases expression, increases expression	3
entinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
resorcinol	decreases expression	1
pentanal	decreases 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	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
Arsenic Trioxide	decreases response to substance	1
Vorinostat	increases expression	1
Leflunomide	increases expression	1
Air Pollutants	increases expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Drugs, Chinese Herbal	increases expression	1
Estradiol	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methyl Methanesulfonate	increases expression	1
Naphthoquinones	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT05357612	PHASE4	RECRUITING	Characterization of the Serotonin 2A Receptor Selective PET Tracer [18F]MH.MZ in Patients With Neurodegenerative Diseases
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT05508789	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ 5)
NCT05738486	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 6)
NCT06111014	PHASE3	TERMINATED	Continuation Study for Latozinemab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00863538	PHASE2	COMPLETED	Phase II Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01004016	PHASE2	COMPLETED	A Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01350440	PHASE2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT02540655	PHASE2	COMPLETED	Efficacy and Safety Study of Stemchymal® in Polyglutamine Spinocerebellar Ataxia
NCT03932669	PHASE2	COMPLETED	Effect of Nilotinib in Cerebellar Ataxia Patients
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT05125666	PHASE2	UNKNOWN	Efficacy of Dual Task Training on Children With Ataxia After Medulloblastoma Resection
NCT06397274	PHASE2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia
NCT00001365	PHASE2	COMPLETED	Dextromethorphan for the Treatment of Parkinson’s Disease and Similar Conditions of the Nervous System
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00907283	PHASE2	UNKNOWN	Ferrochelating Treatment in Patients Affected by Neurodegeneration With Brain Iron Accumulation (NBIA)
NCT01518374	PHASE2	COMPLETED	Clinical Evaluation of Florbetapir F 18 (18F-AV-45)
NCT02656498	PHASE2	COMPLETED	[18F]THK-5351 Positron Emission Computed Tomography Study of Normal, Mild Cognitive Impairment, Alzheimer’s Disease and Other Neurodegenerative Disease
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03538522	PHASE2	COMPLETED	A Double-Blind, Placebo-Controlled Safety and Efficacy Study of NA-831
NCT04838301	PHASE2	RECRUITING	Allopregnanolone Regenerative Therapeutic for Mild Alzheimer’s Disease
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT05318976	PHASE2	COMPLETED	A Study of XPro1595 in Patients With Early Alzheimer’s Disease With Biomarkers of Inflammation
NCT05321498	PHASE2	WITHDRAWN	Study to Assess the Efficacy of XPro1595 in Patients With Mild Cognitive Impairment With Biomarkers of Inflammation