SERPIND1

Chr 22AD

serpin family D member 1

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

NCBI Gene: 3053 ENSG00000099937 UniProt: P05546 OMIM: 142360

The protein functions as a thrombin inhibitor that is activated by glycosaminoglycans including heparin and dermatan sulfate, and also inhibits chymotrypsin. Mutations cause thrombophilia 10 due to heparin cofactor II deficiency, which follows an autosomal dominant inheritance pattern. The gene shows very low constraint to loss-of-function variation (pLI near zero, LOEUF 1.5), suggesting tolerance to inactivating variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.501 OMIM phenotype

Clinical Summary— SERPIND1

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Gene-Disease Validity (ClinGen)

heparin cofactor 2 deficiency · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

-0.06Z-score

OE missense 1.01 (0.92–1.11)

288 obs / 285.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.97 (0.65–1.50)

0≤0.351.4

Missense OE?1.01 (0.92–1.11)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 15 / 15.4Missense obs/exp: 288 / 285.3Syn Z: -0.90

This gene — mechanism propensity

0.6937th %ile

GOF

0.6639th %ile

LOF

0.2581th %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.