F11

Chr 4

coagulation factor XI

Also known as: FXI, PTA

NCBI Gene: 2160 ENSG00000088926 UniProt: P03951 OMIM: 264900

This gene encodes coagulation factor XI, a serine protease that triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX. Mutations cause factor XI deficiency (Rosenthal syndrome), a bleeding disorder that can be inherited in either autosomal dominant or autosomal recessive patterns. The gene is not highly constrained against loss-of-function variants (pLI near zero), consistent with the viability of individuals with factor XI deficiency.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes coagulation factor XI of the blood coagulation cascade. This protein is present in plasma as a zymogen, which is a unique plasma coagulation enzyme because it exists as a homodimer consisting of two identical polypeptide chains linked by disulfide bonds. During activation of the plasma factor XI, an internal peptide bond is cleaved by factor XIIa (or XII) in each of the two chains, resulting in activated factor XIa, a serine protease composed of two heavy and two light chains held together by disulfide bonds. This activated plasma factor XI triggers the middle phase of the intrisic pathway of blood coagulation by activating factor IX. Defects in this factor lead to Rosenthal syndrome, a blood coagulation abnormality. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.452 OMIM phenotypes

Clinical Summary— F11

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Gene-Disease Validity (ClinGen)

congenital factor XI 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

143 unique Pathogenic / Likely Pathogenic· 177 VUS of 638 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — F11

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.45LOEUF

pLI 0.000

Z-score -0.53

OE 1.10 (0.84–1.45)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.02Z-score

OE missense 1.00 (0.91–1.09)

342 obs / 343.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.10 (0.84–1.45)

0≤0.351.4

Missense OE?1.00 (0.91–1.09)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 37 / 33.7Missense obs/exp: 342 / 343.0Syn Z: -0.49

This gene — mechanism propensity

0.6355th %ile

GOF

0.6639th %ile

LOF

0.3453th %ile

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

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNThree dominant-negative mutations in factor XI-deficient patients1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 21457405 ↗

ClinVar Variant Classifications

638 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47

Likely Pathogenic96

VUS177

Likely Benign243

Benign42

Conflicting28

Pathogenic

Likely Pathogenic

177

VUS

243

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	33	2	12	0	47
Likely Pathogenic	61	27	7	1	96
VUS	1	137	30	9	177
Likely Benign	1	6	102	134	243
Benign	0	1	39	2	42
Conflicting	—				28
Total	96	173	190	146	633

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

View in ClinVar →

43 pathogenic / likely-pathogenic (of 62) ClinVar copy-number / structural variants overlap F11 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →