GeneBe

KRIT1

protein-coding

KRIT1 ankyrin repeat containing, the group of CCM adhesion complex|FERM domain containing|Ankyrin repeat domain containing|MicroRNA protein coding host genes

Gene summary

This gene encodes a protein containing four ankyrin repeats, a band 4.1/ezrin/radixin/moesin (FERM) domain, and multiple NPXY sequences. The encoded protein is localized in the nucleus and cytoplasm. It binds to integrin cytoplasmic domain-associated protein-1 alpha (ICAP1alpha), and plays a critical role in beta1-integrin-mediated cell proliferation. It associates with junction proteins and RAS-related protein 1A (Rap1A), which requires the encoded protein for maintaining the integrity of endothelial junctions. It is also a microtubule-associated protein and may play a role in microtubule targeting. Mutations in this gene result in cerebral cavernous malformations. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]

Previous symbols:
  • CCM1

MANE transcript

NM_194454.3

Inheritance

AD

ClinVar variants

P:383U:228B:111

Top phenotype

Cerebral cavernous malformations 1

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr7:92,197,498-92,246,166

External References & Databases

Ensembl (ENSG00000001631)NCBI Gene (889)OMIM (604214)HGNC:1573GenCCUniProt (O00522)AlphaFoldClinVar (KRIT1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~48.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebral cavernous malformation 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020724

Submitter: Labcorp Genetics (formerly Invitae)

cerebral cavernous malformation 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020724

Submitter: G2P

cerebral cavernous malformation 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020724

Submitter: Genomics England PanelApp

cerebral cavernous malformation 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020724

Submitter: PanelApp Australia

cerebral cavernous malformation 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020724

Submitter: ClinGen

*KRIT1* was first reported in relation to autosomal dominant cerebral cavernous malformation in 1999 (Laberge-le Couteulx et al., PMID:10508515). Germline variation in *KRIT1* accounts for up to 65% of cases of familial cerebral cavernous malformation (PMID: 33651268). *KRIT1* associated cerebral cavernous malformations can also lead to headache, seizure, neurological deficits and sometimes stroke with an age of onset typically in adulthood. 9 variants (6 frameshift and 3 nonsense) that have been reported in 9 probands in 2 publications (PMIDs:10508515, 35444609) are included in this curation. Variants in *KRIT1* have also been shown to segregate with disease in at least one family with 7 segregations between genotype positive individuals with MRI confirmed cerebral cavernous malformations (PMID:35444609). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity appears to be a two-hit mechanism, with a germline LOF variant and somatic LOF variation in the wildtype allele at the site of lesion formation (PMID:24698976). This gene-disease relationship is also supported by coimmunoprecipitation data showing an interaction with *CCM2*, which is curated definitive for cerebral cavernous malformation. Further, a mouse model where heterozygous knock-out of *KRIT1* is crossed in to a background with a homozygous *TP53* knockout (to induce random genetic variation) where cavernous malformations only form when *TP53* is knocked out (PMIDs:17900104, 18981891). In summary, there is definitive evidence supporting the relationship between *KRIT1* and autosomal dominant cerebral cavernous malformation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Neurovascular GCEP on the meeting date October 28, 2026 (SOP Version 12).

famililal cerebral cavernous malformationsSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0031037

Submitter: Orphanet

cerebral cavernous malformation 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020724

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Cerebral cavernous malformations 1AD

Manifestation: Cardiovascular; Dermatologic; Neurologic

Intervention: Cardiovascular; Neurologic; Pharmacogenomic

Rationale: Surveillance measures (eg, spinal cord MRI, annual brain gradient echo or susceptibility-weighted imaging) has been advocated; Agents that increase risk of hemorrhage should be avoided (eg, aspirin, NSAIDs, heparin, warfarin)

Refs: 10508515; 10545614; 10814716; 11222804; 11310633; 11161805; 12404106; 11831930; 11914398; 15079030; 17562932; 17211633; 18060436; 18207546; 19099113; 19453802; 19454328; 20301470; 20306072; 20646827; 20689144; 20884211; 21029238; 22261708; 22510019; 22699465; 23584803; 23663874; 23806994; 23828392; 24007869; 24058906Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KRIT1 variants in ClinVar

14 Conditions Cataloged
Cerebral cavernous malformationTotal: 489
not providedTotal: 262
Inborn genetic diseasesTotal: 170
KRIT1-related disorderTotal: 112
not specifiedTotal: 64
Angiokeratoma corporis diffusum with arteriovenous fistulasTotal: 28
Cerebral cavernous malformation 1Total: 14
Hereditary cavernous hemangioma of brainTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_194454.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
4
clinvar
86
clinvar
 90
missense
3
clinvar
9
clinvar
217
clinvar
25
clinvar
 254
nonsense
85
clinvar
27
clinvar
2
clinvar
 114
start loss
1
clinvar
 1
frameshift
142
clinvar
65
clinvar
1
clinvar
 208
splice donor/acceptor (+/-2bp)
34
clinvar
17
clinvar
4
clinvar
 55
Total2641192281110722

Highest pathogenic variant AF is 0.00001313767

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 115 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_194454.3RefSeqNP_919436.116MANE Select
ENST00000394505.7EnsemblENSP00000378013.216MANE Select
NM_001013406.2RefSeqNP_001013424.115Standard
NM_001350669.1RefSeqNP_001337598.115Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
krit1Danio rerio

Structure: endothelial cell

Quality: increased distribution

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Rap1 signaling pathway - Homo sapiens (human)

Biological Process

  • angiogenesis
  • negative regulation of endothelial cell proliferation
  • small GTPase mediated signal transduction
  • negative regulation of endothelial cell migration
  • negative regulation of angiogenesis

Molecular Function

  • protein binding
  • phosphatidylinositol-4,5-bisphosphate binding
  • microtubule binding
  • GTPase regulator activity
  • protein-containing complex binding

Cellular Component

  • extracellular space
  • cytoplasm
  • microtubule
  • plasma membrane
  • cell-cell junction

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000394507
Coding exons
16
Length
47198
Individuals with no LoFs
125720
Homozygous LoFs
0
Heterozygous LoFs
24
Defined
125744
p
0.0000954
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.433153950.7980.00001984858
Missense (PolyPhen)96135.840.706731706
Synonymous-0.2441291261.030.000005801332
Loss of Function4.181443.80.3190.00000237527

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000970.000097rare
South Asian0.000160.00016rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity (By similarity). Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits ERK1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction, and cell junction stabilization. Plays a role in integrin signaling via its interaction with ITGB1BP1; this prevents the interaction between ITGB1 and ITGB1BP1. Microtubule- associated protein that binds to phosphatidylinositol 4,5- bisphosphate (PIP2)-containing membranes in a GTP-bound RAP1- dependent manner. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels. {ECO:0000250|UniProtKB:Q6S5J6, ECO:0000269|PubMed:11741838, ECO:0000269|PubMed:17916086, ECO:0000269|PubMed:20332120, ECO:0000269|PubMed:20616044, ECO:0000269|PubMed:20668652, ECO:0000269|PubMed:21633110, ECO:0000269|PubMed:23317506}.;
Disease
DISEASE: Cerebral cavernous malformations 1 (CCM1) [MIM:116860]: A congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. {ECO:0000269|PubMed:12172908}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.416

Intolerance Scores

LoFtool
0.845
RVIS EVS
-0.87
RVIS percentile EVS
10.8

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.926

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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