PROS1

Chr 3ADAR

protein S

Also known as: PROS, PS21, PS22, PS23, PS24, PS25, PSA, THPH5

NCBI Gene: 5627 ENSG00000184500 UniProt: P07225 OMIM: 176880

Protein S is a vitamin K-dependent anticoagulant plasma protein that serves as a cofactor for activated protein C in degrading coagulation factors Va and VIIIa to prevent excessive blood clotting. Mutations cause thrombophilia 5 due to protein S deficiency, which can be inherited in either autosomal dominant or autosomal recessive patterns. This gene is not highly constrained against loss-of-function variants, reflecting the fact that partial protein S deficiency is compatible with life but increases thrombotic risk.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a vitamin K-dependent plasma protein that functions as a cofactor for the anticoagulant protease, activated protein C (APC) to inhibit blood coagulation. It is found in plasma in both a free, functionally active form and also in an inactive form complexed with C4b-binding protein. Mutations in this gene result in autosomal dominant hereditary thrombophilia. An inactive pseudogene of this locus is located at an adjacent region on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Oct 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismAD/ARLOEUF 0.572 OMIM phenotypes

Clinical Summary— PROS1

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Gene-Disease Validity (ClinGen)

protein S deficiency · SDDefinitive

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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ClinVar Variants

155 unique Pathogenic / Likely Pathogenic· 298 VUS of 700 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PROS1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.57LOEUF

pLI 0.000

Z-score 3.49

OE 0.35 (0.23–0.57)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.58Z-score

OE missense 0.91 (0.83–1.00)

335 obs / 366.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.23–0.57)

0≤0.351.4

Missense OE?0.91 (0.83–1.00)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 12 / 34.0Missense obs/exp: 335 / 366.5Syn Z: 0.11

This gene — mechanism propensity

0.6453th %ile

GOF

0.5758th %ile

LOF

0.2776th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

700 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic79

Likely Pathogenic76

VUS298

Likely Benign173

Benign17

Conflicting43

Pathogenic

Likely Pathogenic

298

VUS

173

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	53	14	12	0	79
Likely Pathogenic	40	30	6	0	76
VUS	3	235	55	5	298
Likely Benign	0	2	83	88	173
Benign	0	0	15	2	17
Conflicting	—				43
Total	96	281	171	95	686

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap PROS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →