KNG1

Chr 3ARAD

kininogen 1

Also known as: BDK, BK, HAE6, HK, HMWK, KNG

NCBI Gene: 3827 ENSG00000113889 UniProt: P01042 OMIM: 612358

This gene uses alternative splicing to generate two different proteins- high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK). HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. Bradykinin also functions as an antimicrobial peptide with antibacterial and antifungal activity. In contrast to HMWK, LMWK is not involved in blood coagulation. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduces or depletes angiotensin converting enzyme 2 (ACE2), which results in an increase in levels of des-Arg(9)-bradykinin, a bioactive metabolite of bradykinin that is associated with lung injury and inflammation. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2020]

OMIM Research

OMIM ResearchGenerating clinical summary…

DNmechanismAR/ADLOEUF 0.923 OMIM phenotypes

Clinical Summary— KNG1

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Gene-Disease Validity (ClinGen)

congenital high-molecular-weight kininogen deficiency · ARDefinitive

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

9 unique Pathogenic / Likely Pathogenic· 100 VUS of 146 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 1.90

OE 0.63 (0.45–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.11Z-score

OE missense 1.02 (0.93–1.11)

363 obs / 357.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.63 (0.45–0.92)

0≤0.351.4

Missense OE?1.02 (0.93–1.11)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 20 / 31.5Missense obs/exp: 363 / 357.0Syn Z: -0.75

This gene — mechanism propensity

0.7326th %ile

GOF

0.5268th %ile

LOF

0.2678th %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

146 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic2

VUS100

Likely Benign16

Benign11

Pathogenic

Likely Pathogenic

100

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	2	0	0	7
Likely Pathogenic	2	0	0	0	2
VUS	3	97	0	0	100
Likely Benign	0	10	1	5	16
Benign	1	5	0	5	11
Total	11	114	1	10	136

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

View in ClinVar →

43 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap KNG1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →