# NM_031443.4(CCM2):c.55C>A (p.Arg19=)

https://sugi.bio/variant/ccm2-p-arg19

## Summary

**CCM2 p.Arg19= (c.55C>A)** is classified **Likely benign** in CCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-04). Absent from gnomAD v4.1; Associated with cerebral cavernous malformation 2.

**At a glance:** Likely benign · review: Single submitter · rsID rs755800734 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CCM2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Arg19= |
| Coding change (HGVS c.) | c.55C>A |
| MANE Select transcript | [NM_031443](https://www.ncbi.nlm.nih.gov/nuccore/NM_031443) |
| dbSNP | [rs755800734](https://www.ncbi.nlm.nih.gov/snp/rs755800734/) |
| Variant type | single nucleotide variant |
| Location | chr7:45038277-45038277 (GRCh38) |
| ClinVar | [VCV2021488](https://www.ncbi.nlm.nih.gov/clinvar/variation/2021488/) |

**All HGVS expressions:** `LRG_664:g.43090C>A`, `LRG_664t1:c.118C>A`, `LRG_664t2:c.55C>A`, `NC_000007.13:g.45077876C>A`, `NC_000007.14:g.45038277C>A`, `NG_016295.1:g.43090C>A`, `NM_001029835.2:c.118C>A`, `NM_001167934.2:c.31-25641C>A`, `NM_001167935.2:c.55C>A`, `NM_001363458.2:c.55C>A`, `NM_001363459.2:c.31-25641C>A`, `NM_031443.4:c.55C>A`, `NR_030770.2:n.137C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 3.841, GERP 0.504, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.74**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.33 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **19** lies in the 'disordered' region.

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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-08-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cerebral cavernous malformation 2, Familial Cerebral Cavernous Malformation 2.

## Same-residue context {#hotspot}

Residue **19** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CCM2 p.Arg19Ter](/variant/ccm2-p-arg19ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CCM2 variant pages (same residue, condition, or type): [CCM2 p.Arg19Ter](/variant/ccm2-p-arg19ter), [CCM2 c.289-1G>A](/variant/ccm2-c-289-minus-1g-a), [CCM2 c.30+1G>A](/variant/ccm2-c-30-plus-1g-a), [CCM2 c.472+1G>C](/variant/ccm2-c-472-plus-1g-c), [CCM2 c.473-1G>T](/variant/ccm2-c-473-minus-1g-t), [CCM2 c.745+1G>T](/variant/ccm2-c-745-plus-1g-t), [CCM2 p.Arg57Ter](/variant/ccm2-p-arg57ter), [CCM2 p.Gln107Ter](/variant/ccm2-p-gln107ter).

### 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 2021488). 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.*