SERPIND1

Chr 22AD

serpin family D member 1

Also known as: D22S673, HC2, HCF2, HCII, HLS2, LS2, THPH10

NCBI Gene: 3053ENSG00000099937UniProt: P05546

This gene belongs to the serpin gene superfamily. Serpins play roles in many processes including inflammation, blood clotting, and cancer metastasis. Members of this family have highly conserved secondary structures with a reactive center loop that interacts with the protease active site to inhibit protease activity. This gene encodes a plasma serine protease that functions as a thrombin and chymotrypsin inhibitor. The protein is activated by heparin, dermatan sulfate, and glycosaminoglycans. Allelic variations in this gene are associated with heparin cofactor II deficiency. [provided by RefSeq, Jul 2015]

Primary Disease Associations & Inheritance

Thrombophilia 10 due to heparin cofactor II deficiencyMIM #612356
AD
UniProtThrombophilia due to heparin cofactor 2 deficiency
525
ClinVar variants
357
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SERPIND1
🧬
Gene-Disease Validity (ClinGen)
heparin cofactor 2 deficiency · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
357 Pathogenic / Likely Pathogenic· 134 VUS of 525 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.
1.50LOEUF
pLI 0.000
Z-score 0.09
OE 0.97 (0.65–1.50)
Tolerant

Highly tolerant — LoF variants common in population

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.
-0.06Z-score
OE missense 1.01 (0.92–1.11)
288 obs / 285.3 exp
Tolerant

Tolerant to missense variation

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.0.97 (0.65–1.50)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.01 (0.92–1.11)
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.1.11
0≤1.21.6
LoF obs/exp: 15 / 15.4Missense obs/exp: 288 / 285.3Syn Z: -0.90

ClinVar Variant Classifications

525 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic322
Likely Pathogenic35
VUS134
Likely Benign19
Benign10
Conflicting5
322
Pathogenic
35
Likely Pathogenic
134
VUS
19
Likely Benign
10
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
319
0
322
Likely Pathogenic
0
0
35
0
35
VUS
3
59
72
0
134
Likely Benign
0
8
2
9
19
Benign
0
3
2
5
10
Conflicting
—5
Total57143014525

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

View in ClinVar →

Protein Context — Lollipop Plot

SERPIND1 · 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

Thrombophilia 10 due to heparin cofactor II deficiency

MIM #612356

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Proteome Characterization of Glaucoma Aqueous Humor.
Liu X et al.·Mol Cell Proteomics
2021
Unveiling the levels and significance of different serpin family proteins in aqueous humor dynamics.
Williams E et al.·BMC Ophthalmol
2025
Proteomics Analysis of Five Potential Plasma-derived Exosomal Biomarkers for Acute Myocardial Infarction.
Xu S et al.·Curr Med Chem
2025
Plasma Proteomic Profiles Among White and African American Individuals With Monoclonal Gammopathy of Unknown Significance (MGUS) and Multiple Myeloma (MM).
Varga C et al.·Clin Lymphoma Myeloma Leuk
2025
Analysis of the gene expression profile in response to human epididymis protein 4 in epithelial ovarian cancer cells.
Zhu L et al.·Oncol Rep
2016
Pathophysiological mechanisms in severe preeclampsia: role of upregulated proteins in blood pressure, extracellular matrix and immunity.
Pinto-Souza CC et al.·Rev Bras Ginecol Obstet
2025Functional
Oncogenic Mutation BRAF V600E Changes Phenotypic Behavior of THLE-2 Liver Cells through Alteration of Gene Expression.
Śmiech M et al.·Int J Mol Sci
2022
Functional analysis of polymorphisms in the promoter regions of genes on 22q11.
Hoogendoorn B et al.·Hum Mutat
2004Functional
Identification of 5 Gene Signatures in Survival Prediction for Patients with Lung Squamous Cell Carcinoma Based on Integrated Multiomics Data Analysis.
Ma H et al.·Biomed Res Int
2020Cohort
Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance.
Woodward KJ et al.·Mol Genet Genomic Med
2019Case report
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