SERPINI1

Chr 3AD

serpin family I member 1

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

NCBI Gene: 5274 ENSG00000163536 UniProt: Q99574 OMIM: 602445

This gene encodes neuroserpin, a serine protease inhibitor that inhibits plasminogen activators and protects neurons from plasmin-mediated damage while regulating synaptic plasticity. Mutations cause familial encephalopathy with neuroserpin inclusion bodies (FENIB), an autosomal dominant condition characterized by progressive encephalopathy and epilepsy. The gene shows tolerance to loss-of-function variants (low pLI), suggesting the pathology arises through a different mechanism than simple protein loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.641 OMIM phenotype

Clinical Summary— SERPINI1

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Gene-Disease Validity (ClinGen)

progressive myoclonus epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 228 VUS of 405 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.027

Z-score 2.68

OE 0.33 (0.18–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.42Z-score

OE missense 0.92 (0.82–1.03)

194 obs / 211.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.18–0.64)

0≤0.351.4

Missense OE?0.92 (0.82–1.03)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 6 / 18.4Missense obs/exp: 194 / 211.2Syn Z: 0.70

This gene — mechanism propensity

0.7132th %ile

GOF

0.7028th %ile

LOF

0.2093th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

405 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic1

VUS228

Likely Benign124

Benign30

Conflicting9

Pathogenic

Likely Pathogenic

228

VUS

124

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	5	0	0	5
Likely Pathogenic	0	1	0	0	1
VUS	8	198	21	1	228
Likely Benign	0	11	45	68	124
Benign	0	5	22	3	30
Conflicting	—				9
Total	8	220	88	72	397

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap SERPINI1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →