# NM_031443.4(CCM2):c.447del (p.Ala150fs)

https://sugi.bio/variant/ccm2-p-ala150fs

## Summary

**CCM2 p.Ala150fs (c.447del)** is classified **Likely pathogenic** in CCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-18). No gnomAD frequency available for this variant; Associated with CCM2-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2486113704 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CCM2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to CCM2-related disorder.

*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.*

**Support & next steps:** [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.Ala150fs |
| Coding change (HGVS c.) | c.447del |
| MANE Select transcript | [NM_031443](https://www.ncbi.nlm.nih.gov/nuccore/NM_031443) |
| dbSNP | [rs2486113704](https://www.ncbi.nlm.nih.gov/snp/rs2486113704/) |
| Variant type | Deletion |
| Location | chr7:45064621-45064621 (GRCh38) |
| ClinVar | [VCV2636973](https://www.ncbi.nlm.nih.gov/clinvar/variation/2636973/) |

**All HGVS expressions:** `LRG_664:g.69434del`, `LRG_664t1:c.510del`, `LRG_664t2:c.447del`, `NC_000007.13:g.45104220del`, `NC_000007.14:g.45064621del`, `NG_016295.1:g.69434del`, `NM_001029835.2:c.510del`, `NM_001167934.2:c.273del`, `NM_001167935.2:c.447del`, `NM_001363458.2:c.447del`, `NM_001363459.2:c.273del`, `NM_031443.4:c.447del`, `NR_030770.2:n.529del`

## 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 5.825, GERP 0.63, 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 4 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **150** lies in the pid domain.

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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-18.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-10-18 |

## Associated conditions {#conditions}

[CCM2-related disorder](https://sugi.bio/atlas/disease/ccm2-related-disorder/).

**Reported phenotype names (ClinVar):** CCM2-related disorder, CCM2-related condition.

## Similar variants {#similar}

Related CCM2 variant pages (same residue, condition, or type): [CCM2 p.Lys26fs](/variant/ccm2-p-lys26fs), [CCM2 p.Asp230fs](/variant/ccm2-p-asp230fs), [CCM2 p.Ile136fs](/variant/ccm2-p-ile136fs), [CCM2 p.Leu47fs](/variant/ccm2-p-leu47fs), [CCM2 p.Lys30fs](/variant/ccm2-p-lys30fs), [CCM2 p.Gln107Ter](/variant/ccm2-p-gln107ter), [CCM2 p.Lys360Ter](/variant/ccm2-p-lys360ter), [CCM2 c.205-2A>G](/variant/ccm2-c-205-minus-2a-g).

### 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 2636973). 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.*