# NM_194454.3(KRIT1):c.700_703del (p.Phe234fs)

https://sugi.bio/variant/krit1-p-phe234fs

## Summary

**KRIT1 p.Phe234fs (c.700_703del)** is classified **Pathogenic** in KRIT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-23). Associated with cerebral cavernous malformation.

**At a glance:** Pathogenic · review: Multiple submitters · 3 submitters · 1 linked condition

## For patients & families {#patients}

This is a change in the KRIT1 gene that is considered disease-causing, submitted by 3 submitters, and is linked to cerebral cavernous malformation.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | KRIT1 is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [KRIT1](https://sugi.bio/atlas/gene/KRIT1/) |
| Protein change (HGVS p.) | p.Phe234fs |
| Coding change (HGVS c.) | c.700_703del |
| MANE Select transcript | [NM_194454](https://www.ncbi.nlm.nih.gov/nuccore/NM_194454) |
| Variant type | Microsatellite |
| Location | chr7:92235429-92235432 (GRCh38) |
| ClinVar | [VCV3381025](https://www.ncbi.nlm.nih.gov/clinvar/variation/3381025/) |

**All HGVS expressions:** `LRG_650:g.15665TTTG[1]`, `LRG_650t1:c.700_703del`, `NC_000007.13:g.91864743CAAA[1]`, `NC_000007.14:g.92235429CAAA[1]`, `NG_012964.1:g.15665TTTG[1]`, `NM_001013406.2:c.700_703del`, `NM_001350669.1:c.700_703del`, `NM_001350670.1:c.700_703del`, `NM_001350671.1:c.15+102_15+105del`, `NM_001350672.1:c.700_703del`, `NM_001350673.1:c.700_703del`, `NM_001350674.1:c.700_703del`, `NM_001350675.1:c.700_703del`, `NM_001350676.1:c.700_703del`, `NM_001350677.1:c.700_703del`, `NM_001350678.1:c.700_703del`, `NM_001350679.1:c.700_703del`, `NM_001350680.1:c.700_703del`, `NM_001350681.1:c.700_703del`, `NM_001350682.1:c.700_703del`, `NM_001350683.1:c.700_703del`, `NM_001350684.1:c.700_703del`, `NM_001350685.1:c.700_703del`, `NM_001350686.1:c.700_703del`, `NM_001350687.1:c.700_703del`, `NM_001350688.1:c.700_703del`, `NM_001350689.1:c.700_703del`, `NM_001350690.1:c.700_703del`, `NM_001350691.1:c.700_703del`, `NM_001350692.1:c.700_703del`, `NM_001350693.1:c.700_703del`, `NM_001350694.1:c.700_703del`, `NM_001350695.1:c.700_703del`, `NM_001350696.1:c.700_703del`, `NM_001350697.1:c.700_703del`, `NM_004912.4:c.700_703del`, `NM_194454.3:c.700_703del`, `NM_194455.1:c.700_703del`, `NM_194456.1:c.700_703del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 7.594, GERP 3.39, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.69, pLI 0.11437. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 19**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**KRIT1** population constraint: LOEUF 0.69, pLI 0.11437, missense-Z 0.89279. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **234** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 83.01, 57% of residues very-high.

**15 experimental structure(s)** (PDB): [3U7D](https://www.rcsb.org/structure/3U7D), [4DX8](https://www.rcsb.org/structure/4DX8), [4DXA](https://www.rcsb.org/structure/4DXA), [4HDO](https://www.rcsb.org/structure/4HDO), [4HDQ](https://www.rcsb.org/structure/4HDQ), [4JIF](https://www.rcsb.org/structure/4JIF).

## What this gene does {#gene-function}

*Describes the biological roles of KRIT1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** KRIT1's established molecular role includes phosphatidylinositol-4,5-bisphosphate binding.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** phosphatidylinositol-4,5-bisphosphate binding, microtubule binding.

**Biological process:** negative regulation of endothelial cell proliferation, negative regulation of endothelial cell migration, negative regulation of angiogenesis, integrin activation, cell redox homeostasis, regulation of establishment of cell polarity.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-23.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-23 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-03 |

## Associated conditions {#conditions}

[cerebral cavernous malformation](https://sugi.bio/atlas/disease/cerebral-cavernous-malformation/).

**Reported phenotype names (ClinVar):** Cerebral cavernous malformation, not provided, none provided, Cerebral cavernous hemangioma (type), Cerebral cavernous malformations, CAVERNOUS ANGIOMA, FAMILIAL, CAVERNOUS ANGIOMATOUS MALFORMATIONS, CEREBRAL CAPILLARY MALFORMATIONS, Cavernous Hemangioma of Brain.

## Similar variants {#similar}

Related KRIT1 variant pages (same residue, condition, or type): [KRIT1 c.1255-1_1256del](/variant/krit1-c-1255-minus-1-1256del), [KRIT1 c.1730+4_1730+7del](/variant/krit1-c-1730-plus-4-1730-plus-7del), [KRIT1 p.Asn402fs](/variant/krit1-p-asn402fs), [KRIT1 p.Gln401fs](/variant/krit1-p-gln401fs), [KRIT1 p.Gln455fs](/variant/krit1-p-gln455fs), [KRIT1 p.Gln573fs](/variant/krit1-p-gln573fs), [KRIT1 p.Glu567_Ser568insTer](/variant/krit1-p-glu567-ser568inster), [KRIT1 p.His326fs](/variant/krit1-p-his326fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3381025). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*