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…

Primary Disease Associations & Inheritance

Thrombophilia 7 due to antithrombin III deficiencyMIM #613118

ADAR

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hereditary antithrombin deficiency · SD · ClinGen 2020

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.15

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

GeneReview available — SERPINC1

Authoritative clinical overview · Recommended first read

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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

Background carrier burden — how many people carry a rare variant somewhere in SERPINC1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

468 rare PASS variants

Rare truncating (LoF)

1 in 14,000

23 rare PASS variants

Rare synonymous (reference)

1 in 190

225 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SERPINC1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 160	1 in 8,400
South Asian	~43k	1 in 130	≈ 1 in 43,000
Remaining (unassigned)	~30k	1 in 89	≈ 1 in 15,000
European (Finnish)	~27k	1 in 440	≈ 1 in 27,000
Admixed American	~22k	1 in 100	≈ 1 in 22,000
African / African American	~21k	1 in 110	none seen
East Asian	~20k	1 in 97	none seen
Ashkenazi Jewish	~13k	1 in 1,100	none seen
Middle Eastern	~2,884	1 in 120	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.