KRIT1

Chr 7AD

KRIT1 ankyrin repeat containing

Also known as: CAM, CCM1

NCBI Gene: 889 ENSG00000001631 UniProt: O00522 OMIM: 604214

The KRIT1 protein is a crucial regulator of heart and vessel formation that maintains endothelial junction integrity, regulates angiogenesis, and controls cellular reactive oxygen species homeostasis. Mutations cause cerebral cavernous malformations, which are vascular lesions in the brain and spinal cord that can present with seizures, headaches, or neurological deficits. The condition follows autosomal dominant inheritance with reduced penetrance and variable expressivity.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.503 OMIM phenotypes

Clinical Summary— KRIT1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

374 unique Pathogenic / Likely Pathogenic· 271 VUS of 845 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KRIT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.50LOEUF

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?

1.43Z-score

OE missense 0.80 (0.73–0.88)

315 obs / 394.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.21–0.50)

0≤0.351.4

Missense OE?0.80 (0.73–0.88)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 14 / 43.8Missense obs/exp: 315 / 394.9Syn Z: -0.24

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKRIT1-related cerebral cavernous malformationLOFAD

This gene — mechanism propensity

0.5477th %ile

GOF

0.5661th %ile

LOF

0.3744th %ile

The Badonyi & Marsh model scores gain-of-function highest, but genomic evidence most strongly supports loss-of-function (haploinsufficiency) as the primary mechanism.

LOF1 literature citation · 90% of P/LP variants are LoF · LOEUF 0.50

Literature Evidence

LOFOnly the adult patient showed asymptomatic cavernous cerebral malformations on cranial MRI, underlining age-dependent penetrance and haploinsufficiency as pivotal features of patients with KRIT1 mutations.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 17898012 ↗

ClinVar Variant Classifications

845 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic278

Likely Pathogenic96

VUS271

Likely Benign129

Benign24

Conflicting28

278

Pathogenic

Likely Pathogenic

271

VUS

129

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	256	3	19	0	278
Likely Pathogenic	79	7	10	0	96
VUS	3	202	62	4	271
Likely Benign	0	9	45	75	129
Benign	0	0	23	1	24
Conflicting	—				28
Total	338	221	159	80	826

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap KRIT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →