# NM_031443.4(CCM2):c.683_686del (p.Phe228fs)

https://sugi.bio/variant/ccm2-p-phe228fs

## Summary

**CCM2 p.Phe228fs (c.683_686del)** is classified **Pathogenic/Likely pathogenic** in CCM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-20). Very rare (popmax 8.47e-05%, nfe); Associated with cerebral cavernous malformation 2.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1131691538 · 3 submitters · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CCM2 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to cerebral cavernous malformation 2.

*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 | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018313/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CCM2](https://sugi.bio/atlas/gene/CCM2/) |
| Protein change (HGVS p.) | p.Phe228fs |
| Coding change (HGVS c.) | c.683_686del |
| MANE Select transcript | [NM_031443](https://www.ncbi.nlm.nih.gov/nuccore/NM_031443) |
| dbSNP | [rs1131691538](https://www.ncbi.nlm.nih.gov/snp/rs1131691538/) |
| Variant type | Deletion |
| Location | chr7:45069897-45069900 (GRCh38) |
| ClinVar | [VCV429700](https://www.ncbi.nlm.nih.gov/clinvar/variation/429700/) |

**All HGVS expressions:** `LRG_664:g.74712_74715del`, `LRG_664t1:c.746_749del`, `NC_000007.13:g.45109498_45109501del`, `NC_000007.14:g.45069899_45069902del`, `NG_016295.1:g.74712_74715del`, `NM_001029835.2:c.746_749del`, `NM_001167934.2:c.509_512del`, `NM_001167935.2:c.473-2827_473-2824del`, `NM_001363458.2:c.683_686del`, `NM_001363459.2:c.509_512del`, `NM_031443.3:c.683_686delTTCT`, `NM_031443.4:c.683_686del`, `NR_030770.2:n.765_768del`

## 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 10.989, GERP 1.56, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.753, pLI 0.0010505. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 10**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,016 in the highest group · 2/1,461,868 alleles overall — very rare (popmax 8.47e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,506 |
| European (non-Finnish) (grpmax) | 8.47e-05% | 1,180,016 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CCM2** population constraint: LOEUF 0.753, pLI 0.0010505, missense-Z 1.787. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **cerebral cavernous malformation 2** — Definitive (AD)

## Protein context {#protein}

Residue **228** lies in the pid domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 67.48, 24% of residues very-high.

**8 experimental structure(s)** (PDB): [4FQN](https://www.rcsb.org/structure/4FQN), [4TVQ](https://www.rcsb.org/structure/4TVQ), [4WJ7](https://www.rcsb.org/structure/4WJ7), [4Y5O](https://www.rcsb.org/structure/4Y5O), [4YKC](https://www.rcsb.org/structure/4YKC), [4YKD](https://www.rcsb.org/structure/4YKD).

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-20.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Genomics Laboratory, Washington University in St. Louis | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-20 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2015-08-19 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-11-13 |

## Associated conditions {#conditions}

[cerebral cavernous malformation 2](https://sugi.bio/atlas/disease/cerebral-cavernous-malformation-2/).

**Reported phenotype names (ClinVar):** Cerebral cavernous malformation 2, not provided, CCM2-related disorder, none provided, Familial Cerebral Cavernous Malformation 2, CCM2-related condition.

## Similar variants {#similar}

Related CCM2 variant pages (same residue, condition, or type): [CCM2 p.Phe228=](/variant/ccm2-p-phe228), [CCM2 p.Phe228Cys](/variant/ccm2-p-phe228cys), [CCM2 p.Gln218fs](/variant/ccm2-p-gln218fs), [CCM2 p.Glu264fs](/variant/ccm2-p-glu264fs), [CCM2 p.Gly24fs](/variant/ccm2-p-gly24fs), [CCM2 c.804-12del](/variant/ccm2-c-804-minus-12del), [CCM2 p.Ala32fs](/variant/ccm2-p-ala32fs), [CCM2 p.Arg28fs](/variant/ccm2-p-arg28fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 429700). 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.*