SZT2

Summary

SZT2 (SZT2 subunit of KICSTOR complex, HGNC:29040) is a protein-coding gene on chromosome 1p34.2, encoding KICSTOR complex protein SZT2 (Q5T011). As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway.

The protein encoded by this gene is expressed in the brain, predominantly in the parietal and frontal cortex as well as in dorsal root ganglia. It is localized to the peroxisome, and is implicated in resistance to oxidative stress. It likely functions by increasing superoxide dismutase (SOD) activity, but itself has no direct SOD activity. Studies in mice show that this gene confers low seizure threshold, and may also enhance epileptogenesis.

Source: NCBI Gene 23334 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic developmental and epileptic encephalopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 3,546 total — 119 pathogenic, 53 likely-pathogenic
• Phenotypes (HPO): 67
• MANE Select transcript: NM_001365999

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29040
Approved symbol	SZT2
Name	SZT2 subunit of KICSTOR complex
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10387, SZT2B, RP11-506B15.1, FLJ34502, SZT2A, KICS1
Ensembl gene	ENSG00000198198
Ensembl biotype	protein_coding
OMIM	615463
Entrez	23334

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 10 retained_intron, 3 protein_coding, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000357658, ENST00000372450, ENST00000406439, ENST00000460536, ENST00000470139, ENST00000470897, ENST00000471177, ENST00000478140, ENST00000562955, ENST00000634258, ENST00000638263, ENST00000638631, ENST00000638642, ENST00000638769, ENST00000639197, ENST00000639852, ENST00000640484, ENST00000648058, ENST00000649403

RefSeq mRNA: 2 — MANE Select: NM_001365999 NM_001365999, NM_015284

CCDS: CCDS30694, CCDS90935

Canonical transcript exons

ENST00000634258 — 72 exons

Exon	Start	End
ENSE00001249606	43437595	43437700
ENSE00001249659	43445894	43445984
ENSE00001249669	43443597	43443796
ENSE00001249677	43443352	43443477
ENSE00001249685	43443188	43443267
ENSE00001249697	43442819	43443086
ENSE00001249703	43442442	43442618
ENSE00001249711	43442268	43442368
ENSE00001249721	43442000	43442130
ENSE00001249728	43441686	43441818
ENSE00001249736	43441504	43441601
ENSE00001249747	43441214	43441380
ENSE00001249755	43440453	43440586
ENSE00001249762	43439881	43440048
ENSE00001249769	43439605	43439769
ENSE00001249807	43437406	43437508
ENSE00001249813	43437171	43437323
ENSE00001249822	43435200	43435329
ENSE00001249828	43434386	43434485
ENSE00001249839	43432989	43433190
ENSE00001249850	43432728	43432799
ENSE00001249860	43432517	43432604
ENSE00001249868	43432272	43432439
ENSE00001249877	43431716	43431901
ENSE00001249884	43431460	43431523
ENSE00001249892	43431265	43431372
ENSE00001249901	43430949	43431090
ENSE00001249909	43430496	43430789
ENSE00001249927	43430011	43430103
ENSE00001377638	43429703	43429844
ENSE00001410546	43437791	43437902
ENSE00001457811	43450337	43454247
ENSE00001457819	43428240	43428486
ENSE00001457820	43428003	43428118
ENSE00001457821	43427530	43427734
ENSE00002586005	43415960	43416101
ENSE00002608173	43419734	43419944
ENSE00002610424	43416535	43416641
ENSE00002611462	43415082	43415213
ENSE00002611870	43420153	43420323
ENSE00002622834	43420749	43420983
ENSE00003458508	43425835	43425949
ENSE00003458682	43423099	43423316
ENSE00003461600	43422480	43422632
ENSE00003464453	43404380	43404550
ENSE00003467764	43422769	43422883
ENSE00003495208	43448079	43448484
ENSE00003507526	43446179	43446259
ENSE00003517303	43403177	43403302
ENSE00003526932	43438699	43438817
ENSE00003528144	43439358	43439442
ENSE00003533882	43425113	43425207
ENSE00003538517	43438929	43439093
ENSE00003538564	43426715	43426809
ENSE00003558527	43448612	43448728
ENSE00003579695	43427056	43427179
ENSE00003579701	43447849	43447971
ENSE00003606648	43450103	43450171
ENSE00003615023	43426038	43426151
ENSE00003627925	43424217	43424432
ENSE00003639204	43403601	43403774
ENSE00003640694	43425474	43425642
ENSE00003645981	43421174	43421303
ENSE00003647869	43424784	43424862
ENSE00003650545	43446342	43446416
ENSE00003659539	43430311	43430389
ENSE00003668208	43446955	43447168
ENSE00003669864	43422083	43422225
ENSE00003682518	43427281	43427445
ENSE00003684460	43447545	43447698
ENSE00003789874	43426368	43426538
ENSE00003810414	43389899	43389995

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 95.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.6237 / max 128.3385, expressed in 1798 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2518	10.8474	1792
2517	0.7353	411
12045	0.0410	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	95.83	gold quality
sural nerve	UBERON:0015488	95.56	gold quality
granulocyte	CL:0000094	91.10	gold quality
apex of heart	UBERON:0002098	90.41	gold quality
adenohypophysis	UBERON:0002196	90.35	gold quality
right lobe of thyroid gland	UBERON:0001119	90.21	gold quality
left lobe of thyroid gland	UBERON:0001120	89.67	gold quality
right testis	UBERON:0004534	89.67	gold quality
pituitary gland	UBERON:0000007	89.60	gold quality
left testis	UBERON:0004533	89.50	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.34	gold quality
bone marrow cell	CL:0002092	88.94	gold quality
cerebellar hemisphere	UBERON:0002245	88.78	gold quality
thyroid gland	UBERON:0002046	88.65	gold quality
mucosa of stomach	UBERON:0001199	88.59	gold quality
cerebellar cortex	UBERON:0002129	88.59	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.58	gold quality
metanephros cortex	UBERON:0010533	88.24	gold quality
calcaneal tendon	UBERON:0003701	87.89	gold quality
left ovary	UBERON:0002119	87.84	gold quality
left uterine tube	UBERON:0001303	87.75	gold quality
skin of leg	UBERON:0001511	87.69	gold quality
right ovary	UBERON:0002118	87.66	gold quality
transverse colon	UBERON:0001157	87.53	gold quality
right uterine tube	UBERON:0001302	87.52	gold quality
body of stomach	UBERON:0001161	87.51	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.46	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.27	gold quality
lower esophagus	UBERON:0013473	87.26	gold quality
spleen	UBERON:0002106	87.19	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	30.59
E-ANND-3	yes	8.18
E-MTAB-7381	no	398.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

141 targeting SZT2, 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-6873-3P	100.00	71.42	2626
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-609	99.82	64.26	505
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-3934-3P	99.76	65.51	1351

Literature-anchored findings (GeneRIF, showing 14)

• mutations in SZT2 cause a severe type of autosomal-recessive infantile encephalopathy. (PMID:23932106)
• We conclude that the disruption of SZT2 with some residual function might lead to mild or moderate intellectual disability without seizures. (PMID:24324832)
• identification of a protein complex (KICSTOR) that is composed of four proteins, KPTN, ITFG2, C12orf66 and SZT2, and that is required for amino acid or glucose deprivation to inhibit mTORC1 in cultured human cells (PMID:28199306)
• SZT2 has a central role in dictating GATOR-dependent nutrient sensing by promoting lysosomal localization of SZT2-orchestrated GATOR complex, and reveal an unexpected function of lysosome-located GATOR2 in suppressing mTORC1 signalling through SESN recruitment (PMID:28199315)
• in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size. (PMID:28556953)
• SZT2 heterozygote mutation results in early-onset epileptic encephalopathy and leukoencephalopathy. (PMID:29696782)
• results expand the genotype and phenotypes of SZT2-related DEEs, suggesting that SZT2 mutations play a role in developmental delay and epileptic encephalopathy, with high susceptibility to SE and relatively specific MRI findings. (PMID:31397114)
• The loss-of-function nature of SZT2 mutations in the patients, and consequent hyperactivation of mTORC1 signaling in response to both amino acid starvation and stimulation in their lymphoblastoid cell lines, is reported. (PMID:31430354)
• Developmental and epileptic encephalopathy due to SZT2 genomic variants: Emerging features of a syndromic condition. (PMID:32402703)
• A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant. (PMID:33681650)
• The SZT2 Interactome Unravels New Functions of the KICSTOR Complex. (PMID:34685691)
• Genetic analysis of developmental and epileptic encephalopathy caused by novel biallelic SZT2 gene mutations in three Chinese Han infants: a case series and literature review. (PMID:35352205)
• Induced Pluripotent Stem Cell (iPSC) Lines from a Family with Resistant Epileptic Encephalopathy Caused by Compound Heterozygous Mutations in SZT2 Gene. (PMID:36361881)
• Clinical phenotype and genetic characteristics of SZT2 related diseases: A case report and literature review. (PMID:38134649)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000100203
mus_musculus	Szt2	ENSMUSG00000033253
rattus_norvegicus	Szt2	ENSRNOG00000028659
caenorhabditis_elegans		WBGENE00010013

Protein

Protein identifiers

KICSTOR complex protein SZT2 — Q5T011 (reviewed: Q5T011)

Alternative names: Seizure threshold 2 protein homolog

All UniProt accessions (4): A0A0C4DG05, A0A1W2PQY2, A0A1W2PRY5, Q5T011

UniProt curated annotations — full annotation on UniProt →

Function. As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway. Recruits, in an amino acid-independent manner, the GATOR1 complex to the lysosomal membranes and allows its interaction with GATOR2 and the RAG GTPases. Functions upstream of the RAG GTPases and is required to negatively regulate mTORC1 signaling in absence of amino acids. In absence of the KICSTOR complex mTORC1 is constitutively localized to the lysosome and activated. The KICSTOR complex is also probably involved in the regulation of mTORC1 by glucose. May play a role in the cellular response to oxidative stress.

Subunit / interactions. Part of the KICSTOR complex composed of KPTN, ITFG2, KICS2 and SZT2. SZT2 probably serves as a link between the other three proteins in the KICSTOR complex and mediates the direct interaction with the GATOR1 complex.

Subcellular location. Lysosome membrane. Peroxisome.

Tissue specificity. Expressed in the brain, predominantly in the parietal and frontal cortex, as well as in dorsal root ganglia. Expressed in peripheral white blood cells.

Disease relevance. Developmental and epileptic encephalopathy 18 (DEE18) [MIM:615476] A severe autosomal recessive neurologic disorder characterized by lack of psychomotor development apparent from birth, dysmorphic facial features, early onset of refractory seizures, and thick corpus callosum and persistent cavum septum pellucidum on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (4)

UniProt ID	Names	Canonical?
Q5T011-1	1	yes
Q5T011-4	2
Q5T011-5	3
Q5T011-7	4

RefSeq proteins (2): NP_001352928, NP_056099 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033228	SZT2	Family

UniProt features (39 total): region of interest 11, compositionally biased region 7, splice variant 6, sequence conflict 6, modified residue 4, sequence variant 4, chain 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
9VAN	ELECTRON MICROSCOPY	2.9
9V80	ELECTRON MICROSCOPY	2.95
9V0J	ELECTRON MICROSCOPY	2.97
9V86	ELECTRON MICROSCOPY	3.04
9V9N	ELECTRON MICROSCOPY	3.08
9V6E	ELECTRON MICROSCOPY	3.19
9O5A	ELECTRON MICROSCOPY	3.2
9O5D	ELECTRON MICROSCOPY	3.34
9O5E	ELECTRON MICROSCOPY	5

Predicted structure (AlphaFold)

No AlphaFold model available for Q5T011 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (4): 1276, 1416, 1641, 1651

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9639288	Amino acids regulate mTORC1
R-HSA-2262752	Cellular responses to stress
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711097	Cellular response to starvation

MSigDB gene sets: 280 (showing top): FREAC2_01, CCAWYNNGAAR_UNKNOWN, GOCC_VACUOLAR_MEMBRANE, GCANCTGNY_MYOD_Q6, GOBP_REGULATION_OF_OXIDOREDUCTASE_ACTIVITY, GOBP_NEUROGENESIS, FOXO4_01, FOXO1_01, CCATCCA_MIR432, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_LYSOSOME, COUP_01, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_PIGMENTATION, MODULE_195

GO Biological Process (10): central nervous system development (GO:0007417), post-embryonic development (GO:0009791), corpus callosum morphogenesis (GO:0021540), cellular response to amino acid starvation (GO:0034198), cellular response to glucose starvation (GO:0042149), pigmentation (GO:0043473), protein localization to lysosome (GO:0061462), regulation of superoxide dismutase activity (GO:1901668), negative regulation of TORC1 signaling (GO:1904262), response to nutrient levels (GO:0031667)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (7): lysosomal membrane (GO:0005765), peroxisome (GO:0005777), KICSTOR complex (GO:0140007), lysosome (GO:0005764), membrane (GO:0016020), GATOR2 complex (GO:0061700), GATOR1 complex (GO:1990130)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cellular response to starvation	1
Cellular responses to stimuli	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein-containing complex	3
cellular response to starvation	2
Seh1-associated complex	2
nervous system development	1
system development	1
multicellular organism development	1
multicellular organismal process	1
central nervous system projection neuron axonogenesis	1
corpus callosum development	1
response to amino acid starvation	1
biological_process	1
protein localization to vacuole	1
superoxide dismutase activity	1
regulation of oxidoreductase activity	1
negative regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
response to stimulus	1
binding	1
lysosome	1
lytic vacuole membrane	1
microbody	1
lytic vacuole	1
cellular anatomical structure	1

Protein interactions and networks

STRING

546 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SZT2	ITFG2	Q969R8	996
SZT2	KICS2	Q96MD2	996
SZT2	KPTN	Q9Y664	996
SZT2	DEPDC5	O75140	776
SZT2	SESN2	P58004	758
SZT2	SAMTOR	Q1RMZ1	740
SZT2	NPRL2	Q8WTW4	664
SZT2	WDR59	Q6PJI9	656
SZT2	WDR24	Q96S15	625
SZT2	NPRL3	Q12980	624
SZT2	MIOS	Q9NXC5	594
SZT2	SEH1L	Q96EE3	573
SZT2	TBC1D7	Q9P0N9	511
SZT2	CASTOR1	Q8WTX7	507
SZT2	SEC13	P55735	478
SZT2	SLC38A9	Q8NBW4	478

IntAct

30 interactions, top by confidence:

A	B	Type	Score
NPRL2	NPRL3	psi-mi:“MI:0914”(association)	0.850
NPRL2	NPRL3	psi-mi:“MI:0403”(colocalization)	0.850
MIOS	SEC13	psi-mi:“MI:0914”(association)	0.790
NPRL2	DEPDC5	psi-mi:“MI:0914”(association)	0.730
SAMTOR	DEPDC5	psi-mi:“MI:0914”(association)	0.640
WDR24	NPRL3	psi-mi:“MI:0914”(association)	0.600
SZT2	WDR24	psi-mi:“MI:0915”(physical association)	0.600
SESN2	NPRL3	psi-mi:“MI:0914”(association)	0.530
SZT2	DEPDC5	psi-mi:“MI:0914”(association)	0.530
ITFG2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
SAMTOR	PER1	psi-mi:“MI:0914”(association)	0.530
KPTN	EIF4G3	psi-mi:“MI:0914”(association)	0.530
ITFG2	DEPDC5	psi-mi:“MI:0914”(association)	0.530
SZT2	NPRL3	psi-mi:“MI:0914”(association)	0.500
SZT2	NPRL3	psi-mi:“MI:0915”(physical association)	0.500
SZT2	SEC13	psi-mi:“MI:0914”(association)	0.350
LAMP1	NPRL3	psi-mi:“MI:0403”(colocalization)	0.350
LAMP1	SZT2	psi-mi:“MI:0403”(colocalization)	0.350
DUSP16	MEIOC	psi-mi:“MI:0914”(association)	0.350
DOCK5	DPYSL4	psi-mi:“MI:0914”(association)	0.350
CD3D	CLGN	psi-mi:“MI:0914”(association)	0.350
C1QTNF2	COL2A1	psi-mi:“MI:0914”(association)	0.350
DEPDC5	GLA	psi-mi:“MI:0914”(association)	0.350
TSGA10IP	BRCA2	psi-mi:“MI:0914”(association)	0.350
KPTN	ALDH1A2	psi-mi:“MI:0914”(association)	0.350
INSR	RIMOC1	psi-mi:“MI:0914”(association)	0.350
LAMP2	SZT2	psi-mi:“MI:0403”(colocalization)	0.270

BioGRID (72): SZT2 (Two-hybrid), SZT2 (Two-hybrid), SZT2 (Two-hybrid), SZT2 (Affinity Capture-RNA), SZT2 (Affinity Capture-MS), SZT2 (Affinity Capture-MS), SZT2 (Affinity Capture-MS), SZT2 (Affinity Capture-MS), SZT2 (Affinity Capture-MS), SZT2 (Affinity Capture-MS), SZT2 (Affinity Capture-MS), SZT2 (Affinity Capture-MS), SZT2 (Affinity Capture-MS), SZT2 (Affinity Capture-MS), SZT2 (Affinity Capture-MS)

ESM2 similar proteins: A0JMW6, A1L1L2, A1L2I9, A2A9C3, A4FV45, A8C756, B0I564, D3ZND0, E9Q2M9, G3HQ82, O15360, O35821, O70576, O75800, Q15021, Q1JPG0, Q24JP3, Q4KLN4, Q5T011, Q5U1Z0, Q5U249, Q66H56, Q6AXZ5, Q6GPP1, Q6NUQ4, Q6NXR4, Q6ZS81, Q7L4E1, Q8BGI5, Q8BK03, Q8BM55, Q8BMG7, Q8BTG3, Q8C3S2, Q8CJF7, Q8K2Z4, Q8K368, Q8WYP5, Q92574, Q99M76

Diamond homologs: A2A9C3, Q5T011

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SZT2	“form complex”	“KICSTOR complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 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
Amino acids regulate mTORC1	10	87.1×	9e-16
Cellular response to starvation	6	43.2×	4e-07
Cellular responses to stress	6	9.6×	2e-03
Cellular responses to stimuli	6	8.2×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of TORC1 signaling	10	111.8×	2e-16
cellular response to amino acid starvation	9	98.7×	2e-14
positive regulation of TORC1 signaling	5	51.0×	4e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

3546 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	119
Likely pathogenic	53
Uncertain significance	1659
Likely benign	1463
Benign	67

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068654	NM_001365999.1(SZT2):c.4742C>G (p.Ser1581Ter)	Pathogenic
1069948	NM_001365999.1(SZT2):c.6126G>A (p.Trp2042Ter)	Pathogenic
1072312	NM_001365999.1(SZT2):c.5630_5633del (p.Asp1877fs)	Pathogenic
1073134	NM_001365999.1(SZT2):c.5188dup (p.Ser1730fs)	Pathogenic
1076278	NM_001365999.1(SZT2):c.8869C>T (p.Arg2957Ter)	Pathogenic
1365482	NM_001365999.1(SZT2):c.1979del (p.Pro660fs)	Pathogenic
1369411	NM_001365999.1(SZT2):c.1086C>G (p.Tyr362Ter)	Pathogenic
1382600	NM_001365999.1(SZT2):c.7280_7281del (p.Pro2427fs)	Pathogenic
1388368	NM_001365999.1(SZT2):c.8285del (p.Phe2762fs)	Pathogenic
1393129	NM_001365999.1(SZT2):c.7123C>T (p.Arg2375Ter)	Pathogenic
1409683	NM_001365999.1(SZT2):c.82C>T (p.Arg28Ter)	Pathogenic
1423687	NM_001365999.1(SZT2):c.8811dup (p.Ser2938fs)	Pathogenic
1440658	NM_001365999.1(SZT2):c.5440del (p.Glu1814fs)	Pathogenic
1446978	NM_001365999.1(SZT2):c.4816C>T (p.Arg1606Ter)	Pathogenic
1452286	NM_001365999.1(SZT2):c.1796dup (p.Ser601fs)	Pathogenic
1452569	NM_001365999.1(SZT2):c.7080G>A (p.Trp2360Ter)	Pathogenic
1453817	NM_001365999.1(SZT2):c.7275del (p.Ala2426fs)	Pathogenic
1453906	NM_001365999.1(SZT2):c.8094_8095dup (p.Lys2699fs)	Pathogenic
1454665	NM_001365999.1(SZT2):c.3946_3947del (p.Gln1316fs)	Pathogenic
1454666	NM_001365999.1(SZT2):c.409C>T (p.Arg137Ter)	Pathogenic
1455695	NM_001365999.1(SZT2):c.5421_5422dup (p.Ala1808fs)	Pathogenic
1456246	NM_001365999.1(SZT2):c.7735C>T (p.Gln2579Ter)	Pathogenic
1457934	NM_001365999.1(SZT2):c.6361C>T (p.Arg2121Ter)	Pathogenic
1737594	NM_001365999.1(SZT2):c.4249_4250del (p.Leu1417fs)	Pathogenic
1744286	NM_001365999.1(SZT2):c.5113del (p.Met1705fs)	Pathogenic
1793956	NM_001365999.1(SZT2):c.2621dup (p.His875fs)	Pathogenic
1910503	NM_001365999.1(SZT2):c.6282C>G (p.Tyr2094Ter)	Pathogenic
1959973	NM_001365999.1(SZT2):c.7579C>T (p.Gln2527Ter)	Pathogenic
1961111	NM_001365999.1(SZT2):c.6178dup (p.Val2060fs)	Pathogenic
1990535	NM_001365999.1(SZT2):c.9040C>T (p.Arg3014Ter)	Pathogenic

SpliceAI

13142 predictions. Top by Δscore:

Variant	Effect	Δscore
1:43403171:TCCCA:T	acceptor_loss	1.0000
1:43403172:CCCA:C	acceptor_loss	1.0000
1:43403173:CCAG:C	acceptor_loss	1.0000
1:43403174:CAG:C	acceptor_loss	1.0000
1:43415209:GCCAG:G	donor_gain	1.0000
1:43415214:G:GC	donor_loss	1.0000
1:43415215:T:G	donor_loss	1.0000
1:43416637:TCCAG:T	donor_loss	1.0000
1:43416638:CCAGG:C	donor_loss	1.0000
1:43416639:CAGGT:C	donor_loss	1.0000
1:43416640:AG:A	donor_loss	1.0000
1:43416641:GG:G	donor_loss	1.0000
1:43416642:GTGA:G	donor_loss	1.0000
1:43416643:T:G	donor_loss	1.0000
1:43420135:T:G	acceptor_gain	1.0000
1:43420140:A:AG	acceptor_gain	1.0000
1:43420140:ACT:A	acceptor_gain	1.0000
1:43420140:ACTG:A	acceptor_gain	1.0000
1:43420141:C:G	acceptor_gain	1.0000
1:43420142:T:TA	acceptor_gain	1.0000
1:43420143:G:A	acceptor_gain	1.0000
1:43420148:TCCA:T	acceptor_loss	1.0000
1:43420149:CCA:C	acceptor_loss	1.0000
1:43420150:CAG:C	acceptor_loss	1.0000
1:43420151:A:AG	acceptor_gain	1.0000
1:43420152:G:GG	acceptor_gain	1.0000
1:43420321:AAG:A	donor_gain	1.0000
1:43420321:AAGGT:A	donor_loss	1.0000
1:43420322:AG:A	donor_gain	1.0000
1:43420323:GG:G	donor_gain	1.0000

AlphaMissense

22101 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:43420784:T:A	W433R	1.000
1:43420784:T:C	W433R	1.000
1:43422140:T:A	W562R	1.000
1:43422140:T:C	W562R	1.000
1:43435219:T:C	L1975P	1.000
1:43437243:T:C	F2036S	1.000
1:43437465:T:C	F2083L	1.000
1:43437467:T:A	F2083L	1.000
1:43437467:T:G	F2083L	1.000
1:43437469:T:A	V2084D	1.000
1:43437505:T:C	L2096P	1.000
1:43403752:T:C	L102P	0.999
1:43403754:A:C	S103R	0.999
1:43403756:C:A	S103R	0.999
1:43403756:C:G	S103R	0.999
1:43416059:G:C	G244R	0.999
1:43416550:C:A	T263K	0.999
1:43416555:G:T	G265W	0.999
1:43416607:T:C	L282P	0.999
1:43419768:G:A	G305D	0.999
1:43419819:G:A	G322E	0.999
1:43420282:T:C	L407P	0.999
1:43420285:G:C	R408P	0.999
1:43420290:G:C	G410R	0.999
1:43420293:T:G	Y411D	0.999
1:43420773:T:C	L429P	0.999
1:43420779:T:C	L431P	0.999
1:43420808:T:G	Y441D	0.999
1:43420880:G:C	G465R	0.999
1:43420943:C:A	R486S	0.999

dbSNP variants (sampled 300 via entrez): RS1000003861 (1:43439667 T>C), RS1000070970 (1:43389376 T>C), RS1000118571 (1:43429411 G>A), RS1000176633 (1:43427442 A>G), RS1000212315 (1:43416096 G>A), RS1000284440 (1:43445920 T>C), RS1000292974 (1:43435123 A>G), RS1000303616 (1:43392263 T>C), RS1000384094 (1:43395977 C>G), RS1000399958 (1:43404616 C>T), RS1000412458 (1:43398260 T>C,G), RS1000507774 (1:43428841 C>A), RS1000520150 (1:43429043 G>A), RS1000525536 (1:43410847 C>T), RS1000535646 (1:43411131 G>A)

Disease associations

OMIM: gene MIM:615463 | disease phenotypes: MIM:615476, MIM:270970, MIM:117100, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 18	Definitive	Autosomal recessive
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Definitive	AR

Mondo (9): developmental and epileptic encephalopathy, 18 (MONDO:0014201), developmental and epileptic encephalopathy (MONDO:0100620), obesity disorder (MONDO:0011122), generalized epilepsy (MONDO:0100574), intellectual disability (MONDO:0001071), hereditary spherocytosis type 3 (MONDO:0010053), self-limited epilepsy with centrotemporal spikes (MONDO:0007295), developmental and epileptic encephalopathy, 1 (MONDO:0010632), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (6): OBSOLETE: Early infantile epileptic encephalopathy without suppression burst (Orphanet:369894), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Hereditary spherocytosis (Orphanet:822), Self-limited epilepsy with centrotemporal spikes (Orphanet:1945), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001315	Reduced tendon reflexes
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001508	Failure to thrive

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST006624_117	Systolic blood pressure	1.000000e-19
GCST007267_195	Systolic blood pressure	2.000000e-08
GCST009600_66	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	1.000000e-08
GCST010002_357	Refractive error	3.000000e-13
GCST010083_237	Hemoglobin levels	2.000000e-11
GCST010696_6	Cortical thickness (min-P)	3.000000e-08
GCST010697_32	Cortical surface area (min-P)	4.000000e-08
GCST010698_63	Subcortical volume (min-P)	3.000000e-09
GCST010699_87	Brain morphology (min-P)	9.000000e-14
GCST010700_24	Cortical thickness (MOSTest)	1.000000e-10
GCST010701_5	Cortical surface area (MOSTest)	1.000000e-08
GCST010702_132	Subcortical volume (MOSTest)	8.000000e-15
GCST010703_201	Brain morphology (MOSTest)	1.000000e-11
GCST90002393_26	Monocyte count	6.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004509	hemoglobin measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0005091	monocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C567489	Spherocytosis, Type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	decreases reaction, affects binding	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	decreases expression	1
butylbenzyl phthalate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Doxorubicin	decreases expression	1
Ozone	affects expression, increases abundance	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	increases methylation	1
Gold Compounds	increases expression	1
Cadmium Chloride	increases expression	1

Cellosaurus cell lines

4 cell lines: 3 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D6L3	iPSC STZ2 II.4 Mut1/Mut2	Induced pluripotent stem cell	Male
CVCL_D6L4	iPSC SZT2 I.I +/Mut1	Induced pluripotent stem cell	Male
CVCL_D6L5	iPSC SZT2 I.II +/Mut2	Induced pluripotent stem cell	Female
CVCL_TR40	HAP1 SZT2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition
NCT00585182	PHASE4	COMPLETED	Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00636142	PHASE4	COMPLETED	Effects of Infliximab on Insulin Sensitivity and Beta Cell Function in Insulin Resistant Human Obesity
NCT00675987	PHASE4	COMPLETED	A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients
NCT00694811	PHASE4	COMPLETED	Effects of Re-Feeding Duration on Weight Maintenance After Weight Loss With Very-Low-Energy Diets (VLEDs)
NCT00699413	PHASE4	TERMINATED	Supplements for Controlling Resistance to Insulin
NCT00729963	PHASE4	COMPLETED	Sibutramine Versus Continuous Positive Airway Pressure (CPAP)in Obstructive Sleep Apnea (OSA) Patients