KRIT1

Chr 7

KRIT1 ankyrin repeat containing

Also known as: CAM, CCM1

NCBI Gene: 889ENSG00000001631UniProt: O00522

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]

Primary Disease Associations & Inheritance

UniProtCerebral cavernous malformations 1
484
ClinVar variants
225
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— KRIT1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
225 Pathogenic / Likely Pathogenic· 167 VUS of 484 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.50LOEUF
pLI 0.001
Z-score 4.18
OE 0.32 (0.21–0.50)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.43Z-score
OE missense 0.80 (0.73–0.88)
315 obs / 394.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.32 (0.21–0.50)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.73–0.88)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03
0≤1.21.6
LoF obs/exp: 14 / 43.8Missense obs/exp: 315 / 394.9Syn Z: -0.24

ClinVar Variant Classifications

484 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic158
Likely Pathogenic67
VUS167
Likely Benign69
Benign10
Conflicting13
158
Pathogenic
67
Likely Pathogenic
167
VUS
69
Likely Benign
10
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
90
3
65
0
158
Likely Pathogenic
45
1
21
0
67
VUS
1
149
15
2
167
Likely Benign
0
3
20
46
69
Benign
0
0
10
0
10
Conflicting
—13
Total13615613148484

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

View in ClinVar →

Protein Context — Lollipop Plot

KRIT1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

KRIT1-related cerebral cavernous malformation

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — KRIT1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Cerebral cavernous malformations - An overview on genetics, clinical aspects and therapeutic strategies.
Dulamea AO et al.·J Neurol Sci
2024Review
KRIT1 in vascular biology and beyond.
Glading AJ·Biosci Rep
2024Review
Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations.
Pham VC et al.·EMBO Mol Med
2024
[Cerebral cavernous malformations].
Koht J et al.·Tidsskr Nor Laegeforen
2005Review
KRIT1 heterozygous mutations are sufficient to induce a pathological phenotype in patient-derived iPSC models of cerebral cavernous malformation.
Arce M et al.·Cell Rep
2025Functional
Genetics of cavernous angiomas.
Labauge P et al.·Lancet Neurol
2007Review
STRIPAK complexes: structure, biological function, and involvement in human diseases.
Hwang J et al.·Int J Biochem Cell Biol
2014Review
Improving clinical interpretation of five KRIT1 and PDCD10 intronic variants.
Fusco C et al.·Clin Genet
2021
Focused ultrasound-microbubble treatment arrests the growth and formation of cerebral cavernous malformations.
Fisher DG et al.·Nat Biomed Eng
2025
Molecular diagnosis in cerebral cavernous malformations.
Mondejar R et al.·Neurologia
2017Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Dual recruitment of two CCM2 molecules to KRIT1 suppresses KLF4 expression.
Huet-Calderwood C et al.·Nat Commun
2026
Possible correlation between KRIT1 variant and non-atherosclerotic vasculopathy resulting in ischemic stroke.
Marzioglu Ozdemir E et al.·Neurol Sci
2026
PTEN/PKM2/ERα-Driven Glyoxalase 1 Overexpression Sustains PC3 Prostate Cancer Cell Growth Through MG-H1/RAGE Pathway Desensitization Leading to H2O2-Dependent KRIT1 Downregulation.
Manfredelli D et al.·Antioxidants (Basel)
2025🔓 Open Access
Familial cerebral cavernous malformations caused by a novel germline structural variant in the KRIT1 gene.
Pilz RA et al.·Neurogenetics
2025🔓 Open Access
Silencing KRIT1 Partially Reverses the Effects of Disturbed Flow on the Endothelial Cell Transcriptome.
Meecham A et al.·Int J Mol Sci
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools