SERPINI1

Chr 3AD

serpin family I member 1

Also known as: HNS-S1, HNS-S2, PI12, neuroserpin

NCBI Gene: 5274ENSG00000163536UniProt: Q99574

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. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Encephalopathy, familial, with neuroserpin inclusion bodiesMIM #604218
AD
425
ClinVar variants
28
Pathogenic / LP
0.03
pLI score
0
Active trials
Clinical Summary— SERPINI1
🧬
Gene-Disease Validity (ClinGen)
progressive myoclonus epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 234 VUS of 425 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.64LOEUF
pLI 0.027
Z-score 2.68
OE 0.33 (0.18–0.64)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.42Z-score
OE missense 0.92 (0.82–1.03)
194 obs / 211.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.33 (0.18–0.64)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.82–1.03)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89
0≤1.21.6
LoF obs/exp: 6 / 18.4Missense obs/exp: 194 / 211.2Syn Z: 0.70

ClinVar Variant Classifications

425 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26
Likely Pathogenic2
VUS234
Likely Benign124
Benign30
Conflicting9
26
Pathogenic
2
Likely Pathogenic
234
VUS
124
Likely Benign
30
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
5
21
0
26
Likely Pathogenic
0
1
1
0
2
VUS
5
198
30
1
234
Likely Benign
0
11
45
68
124
Benign
0
5
22
3
30
Conflicting
—9
Total522011972425

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SERPINI1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Encephalopathy, familial, with neuroserpin inclusion bodies

MIM #604218

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Role of SERPINI1 pathogenic variants in familial encephalopathy with neuroserpin inclusion bodies: A case report and literature review.
Yang X et al.·Seizure
2022Review
Unveiling the levels and significance of different serpin family proteins in aqueous humor dynamics.
Williams E et al.·BMC Ophthalmol
2025
Long non-coding RNA PVT1-mediated miR-543/SERPINI1 axis plays a key role in the regulatory mechanism of ovarian cancer.
Qu C et al.·Biosci Rep
2020Functional
SERPINI1 regulates epithelial-mesenchymal transition in an orthotopic implantation model of colorectal cancer.
Matsuda Y et al.·Cancer Sci
2016Functional
SERPINI1 pathogenic variants: An emerging cause of childhood-onset progressive myoclonic epilepsy.
Ranza E et al.·Am J Med Genet A
2017Case report
Early-onset rapidly progressive myoclonic epilepsy associated with G392R likely pathogenic variant in SERPINI1.
Kara B et al.·Seizure
2020Case report
A Customized Next-Generation Sequencing-Based Panel to Identify Novel Genetic Variants in Dementing Disorders: A Pilot Study.
Lanza G et al.·Neural Plast
2020
A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.
Muona M et al.·Nat Genet
2015
Frontal deficits and atrophy in a patient with familial encephalopathy with neuroserpin inclusion bodies detected by single-case voxel-based morphometry: a case report.
Handa H et al.·BMC Neurol
2024Case report
Whole-transcriptomic Profile of SK-MEL-3 Melanoma Cells Treated with the Histone Deacetylase Inhibitor: Trichostatin A.
Mazzio EA et al.·Cancer Genomics Proteomics
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools