SERPINF2

Chr 17AR

serpin family F member 2

Also known as: A2AP, AAP, ALPHA-2-PI, API, PLI, alpha2AP

NCBI Gene: 5345 ENSG00000167711 UniProt: P08697 OMIM: 613168

This protein is a serine protease inhibitor that serves as the major inhibitor of plasmin, thereby regulating fibrin degradation and blood clotting. Mutations cause alpha-2-plasmin inhibitor deficiency, an autosomal recessive bleeding disorder characterized by severe hemorrhagic diathesis due to impaired regulation of the coagulation pathway. The gene shows tolerance to loss-of-function variants (low pLI), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the serpin family of serine protease inhibitors. The protein is a major inhibitor of plasmin, which degrades fibrin and various other proteins. Consequently, the proper function of this gene has a major role in regulating the blood clotting pathway. Mutations in this gene result in alpha-2-plasmin inhibitor deficiency, which is characterized by severe hemorrhagic diathesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.631 OMIM phenotype

Clinical Summary— SERPINF2

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Gene-Disease Validity (ClinGen)

alpha-2-plasmin inhibitor deficiency · ARDefinitive

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

7 unique Pathogenic / Likely Pathogenic· 60 VUS of 114 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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?

0.63LOEUF

pLI 0.014

Z-score 2.83

OE 0.33 (0.19–0.63)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.23Z-score

OE missense 0.80 (0.71–0.89)

229 obs / 287.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.19–0.63)

0≤0.351.4

Missense OE?0.80 (0.71–0.89)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 7 / 21.0Missense obs/exp: 229 / 287.8Syn Z: -0.13

This gene — mechanism propensity

0.7327th %ile

GOF

0.73top 25%

LOF

0.1994th %ile

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

GOFprediction above median

DNprediction 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

114 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic1

VUS60

Likely Benign26

Benign11

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	2	2	0	6
Likely Pathogenic	1	0	0	0	1
VUS	0	59	1	0	60
Likely Benign	0	7	7	12	26
Benign	0	3	6	2	11
Conflicting	—				4
Total	3	71	16	14	108

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

View in ClinVar →

78 pathogenic / likely-pathogenic (of 93) ClinVar copy-number / structural variants overlap SERPINF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →