SERPINC1

Chr 1ADAR

serpin family C member 1

Also known as: AT3, AT3D, ATIII, ATIII-R2, ATIII-T1, ATIII-T2, THPH7

NCBI Gene: 462 ENSG00000117601 UniProt: P01008 OMIM: 107300

Antithrombin III is a plasma serine protease inhibitor that regulates the blood coagulation cascade by inhibiting thrombin and other activated clotting factors (IXa, Xa, XIa), with activity enhanced by heparin. Mutations cause thrombophilia due to antithrombin III deficiency, which creates a strong predisposition to thrombotic events and can be inherited in either autosomal dominant or recessive patterns. This gene is highly constrained against loss-of-function variants, reflecting its critical role in maintaining hemostatic balance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene, antithrombin III, is a plasma protease inhibitor and a member of the serpin superfamily. This protein inhibits thrombin as well as other activated serine proteases of the coagulation system, and it regulates the blood coagulation cascade. The protein includes two functional domains: the heparin binding-domain at the N-terminus of the mature protein, and the reactive site domain at the C-terminus. The inhibitory activity is enhanced by the presence of heparin. Numerous mutations have been identified for this gene, many of which are known to cause antithrombin-III deficiency which constitutes a strong risk factor for thrombosis. A reduction in the serum level of this protein is associated with severe cases of Coronavirus Disease 19 (COVID-19). [provided by RefSeq, Sep 2020]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.151 OMIM phenotype

Clinical Summary— SERPINC1

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Gene-Disease Validity (ClinGen)

hereditary antithrombin deficiency · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

169 unique Pathogenic / Likely Pathogenic· 160 VUS of 482 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SERPINC1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.15LOEUF

pLI 0.999

Z-score 4.12

OE 0.00 (0.00–0.15)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.36Z-score

OE missense 0.76 (0.68–0.86)

199 obs / 260.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.15)

0≤0.351.4

Missense OE?0.76 (0.68–0.86)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 0 / 19.8Missense obs/exp: 199 / 260.7Syn Z: 0.05

This gene — mechanism propensity

0.3892th %ile

GOF

0.5366th %ile

LOF

0.4332th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF44% of P/LP variants are LoF · LOEUF 0.15

DN1 literature citation

Literature Evidence

DNFull-length antithrombin frameshift variant with aberrant C-terminus causes endoplasmic reticulum retention with a dominant-negative effect1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 36214221 ↗

ClinVar Variant Classifications

482 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic97

Likely Pathogenic72

VUS160

Likely Benign109

Benign19

Conflicting4

Pathogenic

Likely Pathogenic

160

VUS

109

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	46	35	16	0	97
Likely Pathogenic	28	37	7	0	72
VUS	4	139	9	8	160
Likely Benign	0	10	26	73	109
Benign	0	1	13	5	19
Conflicting	—				4
Total	78	222	71	86	461

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

View in ClinVar →

46 pathogenic / likely-pathogenic (of 55) ClinVar copy-number / structural variants overlap SERPINC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →