SERPINI1

Summary

SERPINI1 (serpin family I member 1, HGNC:8943) is a protein-coding gene on chromosome 3q26.1, encoding Neuroserpin (Q99574). Serine protease inhibitor that inhibits plasminogen activators and plasmin but not thrombin.

This gene encodes a member of the serpin superfamily of serine proteinase inhibitors. The protein is primarily secreted by axons in the brain, and preferentially reacts with and inhibits tissue-type plasminogen activator. It is thought to play a role in the regulation of axonal growth and the development of synaptic plasticity. Mutations in this gene result in familial encephalopathy with neuroserpin inclusion bodies (FENIB), which is a dominantly inherited form of familial encephalopathy and epilepsy characterized by the accumulation of mutant neuroserpin polymers. Multiple alternatively spliced variants, encoding the same protein, have been identified.

Source: NCBI Gene 5274 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progressive myoclonus epilepsy (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 406 total — 6 pathogenic
• Phenotypes (HPO): 14
• MANE Select transcript: NM_001122752

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8943
Approved symbol	SERPINI1
Name	serpin family I member 1
Location	3q26.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000163536
Ensembl biotype	protein_coding
OMIM	602445
Entrez	5274

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 16 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000295777, ENST00000446050, ENST00000466865, ENST00000472747, ENST00000472941, ENST00000488374, ENST00000494666, ENST00000872947, ENST00000872948, ENST00000872949, ENST00000872950, ENST00000958447, ENST00000958448, ENST00000958449, ENST00000958450, ENST00000958451, ENST00000958452, ENST00000958453

RefSeq mRNA: 2 — MANE Select: NM_001122752 NM_001122752, NM_005025

CCDS: CCDS3203

Canonical transcript exons

ENST00000446050 — 9 exons

Exon	Start	End
ENSE00001075767	167794620	167794824
ENSE00001075768	167792590	167792784
ENSE00001156147	167825247	167825569
ENSE00001156154	167789111	167789378
ENSE00001813945	167735721	167735823
ENSE00003525050	167807244	167807341
ENSE00003605262	167822986	167823072
ENSE00003632933	167824473	167824562
ENSE00003787408	167790372	167790602

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.3240 / max 875.5705, expressed in 1145 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39663	9.0566	971
39662	0.9299	304
39659	0.6905	117
39661	0.2739	139
39660	0.2347	86
39658	0.1211	67
39664	0.0173	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
frontal pole	UBERON:0002795	99.86	gold quality
orbitofrontal cortex	UBERON:0004167	99.79	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.72	gold quality
middle temporal gyrus	UBERON:0002771	99.70	gold quality
superior frontal gyrus	UBERON:0002661	99.55	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.48	gold quality
prefrontal cortex	UBERON:0000451	99.46	gold quality
postcentral gyrus	UBERON:0002581	99.38	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.37	gold quality
endothelial cell	CL:0000115	99.34	gold quality
parietal lobe	UBERON:0001872	99.31	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.28	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.21	gold quality
frontal cortex	UBERON:0001870	99.12	gold quality
frontal lobe	UBERON:0016525	99.12	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.08	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.98	gold quality
cingulate cortex	UBERON:0003027	98.96	gold quality
anterior cingulate cortex	UBERON:0009835	98.95	gold quality
spinal cord	UBERON:0002240	98.91	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.91	gold quality
substantia nigra pars compacta	UBERON:0001965	98.89	gold quality
neocortex	UBERON:0001950	98.74	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.73	gold quality
cerebral cortex	UBERON:0000956	98.72	gold quality
occipital lobe	UBERON:0002021	98.69	gold quality
subthalamic nucleus	UBERON:0001906	98.64	gold quality
cortical plate	UBERON:0005343	98.63	gold quality
primary visual cortex	UBERON:0002436	98.53	gold quality
entorhinal cortex	UBERON:0002728	98.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	1880.11
E-HCAD-11	yes	22.11
E-GEOD-84465	yes	6.87
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, EGR1, MYC

miRNA regulators (miRDB)

20 targeting SERPINI1, 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-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-1277-5P	100.00	73.95	5056
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-8066	99.05	68.66	1532
HSA-MIR-502-5P	98.77	66.51	906
HSA-MIR-4684-3P	98.24	69.91	1075
HSA-MIR-10397-5P	97.31	69.06	710
HSA-MIR-5579-3P	97.00	68.81	1111
HSA-MIR-6826-5P	93.80	67.42	514

Literature-anchored findings (GeneRIF, showing 39)

• Mutant Neuroserpin (S49P) that causes familial encephalopathy with neuroserpin inclusion bodies is a poor proteinase inhibitor and readily forms polymers in vitro (PMID:11880376)
• The interactions between NSP and t-PA were distinct from those between plasmin and NSP, suggesting that the physiologic effect of t-PA-NSP interactions may be more complex than previously thought. (PMID:12228252)
• Neuroserpin has a role as a selective inhibitor of tissue-type plasminogen activator in the central nervous system [review] (PMID:14983220)
• neuroserpin mutants that cause dementia accumulate as polymers within the endoplasmic reticulum (PMID:15090543)
• tissue plasminogen activator and neuroserpin are widely expressed in the human central nervous system (PMID:15269833)
• reactive centre loop of neuroserpin Portland being partially inserted into beta-sheet A to adopt a conformation similar to an intermediate on the polymerization pathway (PMID:15291813)
• Data show that the S49P mutant of neuroserpin that causes the dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) forms a latent species in vitro and in vivo in addition to the formation of polymers. (PMID:15664988)
• neuroserpin interacts with Abeta(1-42) to form off-pathway non-toxic oligomers and so protects neurons in Alzheimer disease (PMID:16849336)
• intergenic region of the head-to-head PDCD10-SERPINI1 gene pair provides an interesting and informative example of a complex regulatory system (PMID:17212813)
• in a French family with the S52R mutation of the neuroserpin gene, progressive myoclonic epilepsy was associated with a frontal syndrome (PMID:17606885)
• This study provides the first evidence that neuroserpin is associated with early-onset ischemic stroke among Caucasian women. (PMID:17961231)
• conformational modification in the protein under oxidative stress (PMID:18051703)
• We report a neuroserpin mutation that causes electrical status epilepticus of slow-wave sleep. (PMID:18591508)
• Neuroserpin and tissue plasminogen activator are associated with amyloid-beta plaques in Alzheimer brain tissue. (PMID:19222708)
• Human neuroserpin: structure and time-dependent inhibition (PMID:19265707)
• Analyses restricted to glioblastoma (n = 254) yielded significant associations for the SELP, DEFB126/127, SERPINI1, and LY96 genetic regions. (PMID:19423540)
• intracellular neuroserpin polymers activate NF-kappaB by a pathway that is independent of the IRE1, ATF6, and PERK limbs of the canonical unfolded protein response but is dependent on intracellular calcium (PMID:19423713)
• investigated the refolding and polymerization pathways of wild-type neuroserpin and of the pathogenic mutants S49P and H338R (PMID:20691191)
• The latent and polymer hNS forms obtained at 45 degrees C and 85 degrees C differ in their chemical and thermal stabilities; furthermore, the human neuroserpin polymers also differ in size and morphology (PMID:21081089)
• high serum neuroserpin levels before intravenous tPA and neuroserpin levels decrease at 24 h after ischaemic stroke, independently of tPA treatment, may have a role in good functional outcome (PMID:21174006)
• our study did not provide any evidence for an association between genetic variation at the SERPINI1 locus and ischemic stroke (PMID:21487809)
• Hrd1 and gp78 mediate mutant neuroserpin turnover through the ERAD pathway. (PMID:21507957)
• Neuroprotective properties of neuroserpin may be related to the inhibition of excitotoxicity, inflammation, as well as blood brain barrier disruption that occur after acute ischemic stroke. (PMID:21569344)
• the origins of conformational lability (PMID:21961602)
• Alzheimer’s disease brain tissues with elevated neuroserpin protein also showed increased expression of THRbeta1 and HuD (PMID:24036060)
• Molecular Dynamics simulations suggest that Neuroserpin conformational stability and flexibility arise from a spatial distribution of intramolecular salt-bridges and hydrogen bonds. (PMID:25450507)
• Neuroserpin is expressed in naive effector memory and central memory CD4 and CD8 T cell subsets, and monocytes, B cells, and NK cells. T-cell activation caused its translocation to the immunologic synapse, secretion, and delayed downregulation. (PMID:25670787)
• the protective effect of neuroserpin maybe independent from its canonical interaction with a tissue-type plasminogen activator (PMID:26176694)
• The thermal and chemical stability along with the polymerisation propensity of both Wild Type and Glu289Ala NS were characterized. (PMID:26329378)
• This C-terminal lability is not required for neuroserpin polymerisation in the endoplasmic reticulum, but the additional glycan facilitates degradation of the mutant protein during proteasomal impairment. (PMID:26367528)
• SERPINI1 is an important regulator of epithelial-mesenchymal transition in an orthotopic implantation model of colorectal cancer (PMID:26892864)
• Data indicated that rs9853967 and rs11714980 polymorphisms in CCM3 and SERPINI1respectively could be associated with a protective role in cerebral cavernous malformations disease. (PMID:27737651)
• We present two pediatric cases of progressive myoclonic epilepsy with SERPINI1 pathogenic variants that lead to a severe presentation. (PMID:28631894)
• Neuroserpin expression during human brain development and in adult brain revealed by immunohistochemistry and single cell RNA sequencing. (PMID:30644551)
• Deficits in developmental neurogenesis and dendritic spine maturation in mice lacking the serine protease inhibitor neuroserpin. (PMID:31805346)
• Neuroserpin in Bipolar Disorder. (PMID:32003693)
• Contrasting conformational dynamics of beta-sheet A and helix F with implications in neuroserpin inhibition and aggregation. (PMID:33516851)
• Detection of truncated isoforms of human neuroserpin lacking the reactive center loop: Implications in noninhibitory role. (PMID:33893722)
• Role of SERPINI1 pathogenic variants in familial encephalopathy with neuroserpin inclusion bodies: A case report and literature review. (PMID:36417830)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	serpini1	ENSDARG00000034168
mus_musculus	Serpini1	ENSMUSG00000027834
rattus_norvegicus	Serpini1	ENSRNOG00000010248

Paralogs (36): SERPINB1 (ENSG00000021355), SERPINB3 (ENSG00000057149), SERPIND1 (ENSG00000099937), SERPINA4 (ENSG00000100665), SERPINE1 (ENSG00000106366), SERPINI2 (ENSG00000114204), SERPINC1 (ENSG00000117601), SERPINA7 (ENSG00000123561), SERPINB6 (ENSG00000124570), SERPINF1 (ENSG00000132386), AGT (ENSG00000135744), SERPINE2 (ENSG00000135919), SERPINA10 (ENSG00000140093), SERPING1 (ENSG00000149131), SERPINH1 (ENSG00000149257), SERPINA12 (ENSG00000165953), SERPINB7 (ENSG00000166396), SERPINB8 (ENSG00000166401), SERPINB12 (ENSG00000166634), SERPINF2 (ENSG00000167711), SERPINA9 (ENSG00000170054), SERPINA6 (ENSG00000170099), SERPINB9 (ENSG00000170542), SERPINA11 (ENSG00000186910), SERPINA5 (ENSG00000188488), SERPINA3 (ENSG00000196136), SERPINA1 (ENSG00000197249), SERPINB2 (ENSG00000197632), SERPINB13 (ENSG00000197641), SERPINB11 (ENSG00000206072), SERPINB4 (ENSG00000206073), SERPINB5 (ENSG00000206075), HMSD (ENSG00000221887), SERPINB10 (ENSG00000242550), SERPINE3 (ENSG00000253309), SERPINA2 (ENSG00000258597)

Protein

Protein identifiers

Neuroserpin — Q99574 (reviewed: Q99574)

Alternative names: Peptidase inhibitor 12, Serpin I1

All UniProt accessions (5): Q99574, A0A0S2Z455, C9JDY5, C9JQU8, H7C5T9

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease inhibitor that inhibits plasminogen activators and plasmin but not thrombin. May be involved in the formation or reorganization of synaptic connections as well as for synaptic plasticity in the adult nervous system. May protect neurons from cell damage by tissue-type plasminogen activator.

Subunit / interactions. Monomer. Has a tendency to form large polymers already at 41 and 45 degrees Celsius (in vitro).

Subcellular location. Secreted. Cytoplasmic vesicle. Secretory vesicle lumen. Perikaryon.

Tissue specificity. Detected in brain cortex and hippocampus pyramidal neurons (at protein level). Detected in cerebrospinal fluid (at protein level). Predominantly expressed in the brain.

Disease relevance. Encephalopathy, familial, with neuroserpin inclusion bodies (FENIB) [MIM:604218] A neurodegenerative disease clinically characterized by dementia. Additional features include intellectual decline, psychic seizures, progressive myoclonic epilepsy, and cerebral atrophy. Histologically, it is characterized by the presence of eosinophilic inclusion bodies (called Collins bodies) throughout the deeper layers of the cerebral cortex, leading to neuronal death. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the serpin family.

RefSeq proteins (2): NP_001116224, NP_005016 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000215	Serpin_fam	Family
IPR023795	Serpin_CS	Conserved_site
IPR023796	Serpin_dom	Domain
IPR036186	Serpin_sf	Homologous_superfamily
IPR042178	Serpin_sf_1	Homologous_superfamily
IPR042185	Serpin_sf_2	Homologous_superfamily

Pfam: PF00079

UniProt features (48 total): strand 15, helix 13, mutagenesis site 5, turn 4, glycosylation site 4, sequence conflict 2, sequence variant 2, signal peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3F02	X-RAY DIFFRACTION	1.8
3FGQ	X-RAY DIFFRACTION	2.09
3F5N	X-RAY DIFFRACTION	3.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99574-F1	88.79	0.74

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): 362–363 (reactive bond)

Glycosylation sites (4): 157, 321, 401, 403

Mutagenesis-validated functional residues (5):

Position	Phenotype
162	increases protein stability and abolishes tendency to form polymers. no effect on inhibitory activity.
163	increases protein stability and decreases tendency to form polymers. no effect on inhibitory activity.
289	slightly decreases inhibitory activity. no effect on thermal stability.
340	increases protein stability and decreases tendency to form polymers. no effect on inhibitory activity.
161	increases protein stability and abolishes tendency to form polymers. no effect on inhibitory activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 294 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOCC_SECRETORY_GRANULE, HALMOS_CEBPA_TARGETS_UP, SATO_SILENCED_BY_DEACETYLATION_IN_PANCREATIC_CANCER, GOBP_NEUROGENESIS, GGGTGGRR_PAX4_03, chr3q26, TERAMOTO_OPN_TARGETS_CLUSTER_8, MODULE_66, MODULE_120, GERY_CEBP_TARGETS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, MODULE_205, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, KOYAMA_SEMA3B_TARGETS_UP

GO Biological Process (3): central nervous system development (GO:0007417), peripheral nervous system development (GO:0007422), positive regulation of neuron projection development (GO:0010976)

GO Molecular Function (2): serine-type endopeptidase inhibitor activity (GO:0004867), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), secretory granule lumen (GO:0034774), neuronal cell body (GO:0043025), perikaryon (GO:0043204), cytoplasmic vesicle lumen (GO:0060205), extracellular exosome (GO:0070062), extracellular region (GO:0005576), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nervous system development	2
system development	2
cellular anatomical structure	2
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
secretory granule	1
cytoplasmic vesicle lumen	1
somatodendritic compartment	1
cell body	1
neuronal cell body	1
cytoplasmic vesicle	1
vesicle lumen	1
intracellular organelle lumen	1
extracellular vesicle	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

934 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SERPINI1	PLAT	P00750	829
SERPINI1	PLG	P00747	671
SERPINI1	PLAU	P00749	634
SERPINI1	PRNP	P04156	565
SERPINI1	APP	P05067	546
SERPINI1	PDCD10	Q9BUL8	539
SERPINI1	ELANE	P08246	526
SERPINI1	SNCA	P37840	514
SERPINI1	CDIPT	O14735	500
SERPINI1	SERPINA3	P01011	485
SERPINI1	SERPIND1	P05546	458
SERPINI1	NAXE	Q8NCW5	450
SERPINI1	HTT	P42858	433
SERPINI1	PIM1	P11309	423
SERPINI1	TMCO4	Q5TGY1	414

IntAct

7 interactions, top by confidence:

A	B	Type	Score
ELANE	ITIH2	psi-mi:“MI:0914”(association)	0.530
SERPINI1	TSC2	psi-mi:“MI:0915”(physical association)	0.370
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
FURIN	RHOBTB3	psi-mi:“MI:0914”(association)	0.350
SERPINI1	DEDD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (9): SERPINI1 (Biochemical Activity), SERPINI1 (Reconstituted Complex), SERPINI1 (Affinity Capture-MS), SERPINI1 (Two-hybrid), SERPINI1 (Affinity Capture-MS), SERPINI1 (Affinity Capture-MS), SERPINI1 (Affinity Capture-MS), SERPINI1 (Proximity Label-MS), SERPINI1 (Affinity Capture-Western)

ESM2 similar proteins: A2VE14, A5D9H7, B2GV54, B9EKX1, D0RB01, F1M625, F1NBL0, O35684, O54760, O54761, O60242, O60656, O75317, P13591, P31836, P35237, P35290, P62068, P62069, P69849, Q3UQ28, Q3ZCW2, Q4R3G2, Q5JPE7, Q5NVN7, Q5R5K6, Q5R899, Q5RBQ4, Q5RKN4, Q5T4D3, Q5VU57, Q5ZHQ2, Q5ZIN0, Q6ZW05, Q80ZF8, Q8BLF1, Q8BUV3, Q90935, Q90W79, Q969Q5

Diamond homologs: A0A090BX51, A0A0K8RCY5, A0A0K8RJ89, A0A0K8RJV9, A5PJK0, A9RA96, B0CMB0, B1MTB7, B1MTC3, B2KI30, B3RFC3, B4USX2, E2RVI8, O02739, O08800, O35684, O54757, O54758, O54759, O54760, O73790, O73860, O75635, O75830, P01008, P01011, P01012, P01014, P05120, P05619, P12388, P17475, P19104, P22323, P22325, P22922, P23035, P29508, P29524, P30740

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
AMFR	“down-regulates quantity by destabilization”	SERPINI1	polyubiquitination
SYVN1	“down-regulates quantity by destabilization”	SERPINI1	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	0
Uncertain significance	231
Likely benign	117
Benign	28

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1686176	NM_001122752.2(SERPINI1):c.1174G>C (p.Gly392Arg)	Pathogenic
4682580	GRCh37/hg19 3q22.1-29(chr3:132561657-197851986)x3	Pathogenic
7086	NM_001122752.2(SERPINI1):c.145T>C (p.Ser49Pro)	Pathogenic
7087	NM_001122752.2(SERPINI1):c.154A>C (p.Ser52Arg)	Pathogenic
7088	NM_001122752.2(SERPINI1):c.1013A>G (p.His338Arg)	Pathogenic
7090	NM_001122752.2(SERPINI1):c.1174G>A (p.Gly392Arg)	Pathogenic

SpliceAI

1328 predictions. Top by Δscore:

Variant	Effect	Δscore
3:167789105:TTTTA:T	acceptor_loss	1.0000
3:167789106:TTTAG:T	acceptor_loss	1.0000
3:167789107:TTAG:T	acceptor_loss	1.0000
3:167789108:TA:T	acceptor_loss	1.0000
3:167789109:A:AG	acceptor_gain	1.0000
3:167789109:AGGCT:A	acceptor_loss	1.0000
3:167789110:G:GG	acceptor_gain	1.0000
3:167789110:GGCTT:G	acceptor_gain	1.0000
3:167789157:T:A	acceptor_gain	1.0000
3:167789379:G:GG	donor_gain	1.0000
3:167789379:GTA:G	donor_loss	1.0000
3:167790369:CA:C	acceptor_loss	1.0000
3:167790370:A:AG	acceptor_gain	1.0000
3:167790371:G:GC	acceptor_loss	1.0000
3:167790371:G:GG	acceptor_gain	1.0000
3:167790576:A:AG	donor_gain	1.0000
3:167790580:G:GG	donor_gain	1.0000
3:167790600:ACA:A	donor_gain	1.0000
3:167790603:G:GG	donor_gain	1.0000
3:167792781:TATGG:T	donor_loss	1.0000
3:167792782:ATGG:A	donor_loss	1.0000
3:167792783:TGGTA:T	donor_loss	1.0000
3:167792784:GGTAA:G	donor_loss	1.0000
3:167792785:GTAAG:G	donor_loss	1.0000
3:167792786:T:A	donor_loss	1.0000
3:167794616:TTA:T	acceptor_loss	1.0000
3:167794618:A:AG	acceptor_gain	1.0000
3:167794618:AG:A	acceptor_gain	1.0000
3:167794618:AGG:A	acceptor_gain	1.0000
3:167794619:G:GC	acceptor_loss	1.0000

AlphaMissense

2756 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:167792676:T:A	W190R	0.999
3:167792676:T:C	W190R	0.999
3:167792678:G:C	W190C	0.999
3:167792678:G:T	W190C	0.999
3:167792688:T:C	F194L	0.999
3:167792689:T:C	F194S	0.999
3:167792690:T:A	F194L	0.999
3:167792690:T:G	F194L	0.999
3:167792718:T:C	F204L	0.998
3:167792719:T:C	F204S	0.998
3:167792720:C:A	F204L	0.998
3:167792720:C:G	F204L	0.998
3:167794668:T:C	L242P	0.998
3:167794778:T:A	W279R	0.998
3:167794778:T:C	W279R	0.998
3:167825268:G:C	R393P	0.998
3:167792677:G:C	W190S	0.997
3:167792689:T:G	F194C	0.997
3:167794818:T:C	L292P	0.997
3:167794821:C:A	P293H	0.997
3:167824532:T:C	F376L	0.997
3:167824534:T:A	F376L	0.997
3:167824534:T:G	F376L	0.997
3:167792719:T:G	F204C	0.995
3:167792758:T:C	M217T	0.995
3:167825264:G:A	G392R	0.995
3:167825264:G:C	G392R	0.995
3:167794665:T:A	V241D	0.994
3:167794821:C:G	P293R	0.994
3:167807246:T:C	F295S	0.994

dbSNP variants (sampled 300 via entrez): RS1000003342 (3:167735447 G>C), RS1000062460 (3:167820680 C>T), RS1000076429 (3:167734526 G>A,C), RS1000077819 (3:167769258 C>A), RS1000140024 (3:167812188 A>G), RS1000180230 (3:167744667 T>A,C), RS1000189422 (3:167799258 G>C), RS1000212689 (3:167745187 C>G), RS1000274553 (3:167771814 TGTGA>T), RS1000306673 (3:167781468 C>T), RS1000317288 (3:167775206 G>A), RS1000322596 (3:167781862 C>A,T), RS1000353651 (3:167765110 G>A,C), RS1000362492 (3:167738030 T>C), RS1000410080 (3:167824031 C>G,T)

Disease associations

OMIM: gene MIM:602445 | disease phenotypes: MIM:604218

GenCC curated gene-disease

Disease	Classification	Inheritance
familial encephalopathy with neuroserpin inclusion bodies	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
progressive myoclonus epilepsy	Definitive	AD

Mondo (2): familial encephalopathy with neuroserpin inclusion bodies (MONDO:0011412), congenital nervous system disorder (MONDO:0002320)

Orphanet (1): Familial encephalopathy with neuroserpin inclusion bodies (Orphanet:85110)

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000639	Nystagmus
HP:0000651	Diplopia
HP:0000726	Dementia
HP:0001250	Seizure
HP:0001260	Dysarthria
HP:0001298	Encephalopathy
HP:0001336	Myoclonus
HP:0002059	Cerebral atrophy
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002171	Gliosis
HP:0002529	Neuronal loss in central nervous system
HP:0002936	Distal sensory impairment
HP:6001062	Eosinophilic neuronal inclusion bodies

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000175_48	Height	7.000000e-06
GCST001921_2	Heart rate	7.000000e-06
GCST004048_1	Fast beta electroencephalogram	5.000000e-09
GCST007451_1	Skin, hair and eye pigmentation (multivariate analysis)	2.000000e-08
GCST007457_9	Eye color (saturation)	9.000000e-06
GCST008156_47	Hip circumference adjusted for BMI	1.000000e-06
GCST009391_1029	Metabolite levels	7.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004357	electroencephalogram measurement
EFO:0009764	eye colour measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0010540	thiamine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536841	Familial encephalopathy with neuroserpin inclusion bodies (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	9
(+)-JQ1 compound	increases expression	7
Cyclosporine	decreases expression	3
trichostatin A	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Acetaminophen	increases expression	2
Estradiol	affects cotreatment, decreases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Cadmium Chloride	decreases expression, increases abundance	2
Particulate Matter	decreases expression, increases abundance	2
sotorasib	increases expression, affects cotreatment	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
zinc chromate	increases abundance, increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
phenethyl isothiocyanate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, increases expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Sunitinib	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_E4VD	KOLF2.1J SERPINI1 4.6kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_E7M5	KOLF2.1J SERPINI1 S49P SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7M6	KOLF2.1J SERPINI1 S49P SNV/WT	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00916903	Not specified	TERMINATED	Genetic Disease Gene Identification