# NM_000067.3(CA2):c.663+282del

https://sugi.bio/variant/ca2-c-663-plus-282del

## Summary

**CA2 c.663+282del** is classified **Benign** in CA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-16). Common (popmax 9.06%, afr) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Single submitter · rsID rs11452517 · 1 submitter · common (popmax 9.06%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CA2 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter.

*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 | [CA2](https://sugi.bio/atlas/gene/CA2/) |
| Coding change (HGVS c.) | c.663+282del |
| MANE Select transcript | [NM_000067](https://www.ncbi.nlm.nih.gov/nuccore/NM_000067) |
| dbSNP | [rs11452517](https://www.ncbi.nlm.nih.gov/snp/rs11452517/) |
| Variant type | Deletion |
| Location | chr8:85477545-85477545 (GRCh38) |
| ClinVar | [VCV1227991](https://www.ncbi.nlm.nih.gov/clinvar/variation/1227991/) |

**All HGVS expressions:** `NC_000008.10:g.86389786del`, `NC_000008.11:g.85477557del`, `NG_007287.1:g.18541del`, `NM_000067.3:c.663+282del`, `NM_001293675.2:c.360+282del`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 9.06%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -1.843, GERP -1.9 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.399**. 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.*
- Splice region: **deep intronic (+282 nt into the intron)**.
- Non-coding constraint (Gnocchi): **Z 1.65**, o/e 0.87 (1 kb window 85,477,000–85,478,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- 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 **9.06%** (afr) · FAF95 8.82% · FAF99 8.72% · 3,639/40,148 in the highest group · 3,944/146,428 alleles overall — common (popmax 9.06%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 9.06% | 11 |
| Remaining individuals (not grpmax-eligible) | 1.57% | 64 |
| Middle Eastern | 1.41% | 71 |
| Admixed American | 1.17% | 85 |
| South Asian | 0.526% | 190 |
| Finnish (not grpmax-eligible) | 0.236% | 424 |
| East Asian | 0.0994% | 1,006 |
| European (non-Finnish) | 0.0677% | 1,477 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0585% | 1,709 |

*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}

**CA2** population constraint: LOEUF 1.491, pLI 3.9499e-08, missense-Z 0.27169. *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):

- **autosomal recessive osteopetrosis 3** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 97.38, 98% of residues very-high.

**1249 experimental structure(s)** (PDB): [12CA](https://www.rcsb.org/structure/12CA), [1A42](https://www.rcsb.org/structure/1A42), [1AM6](https://www.rcsb.org/structure/1AM6), [1AVN](https://www.rcsb.org/structure/1AVN), [1BCD](https://www.rcsb.org/structure/1BCD), [1BIC](https://www.rcsb.org/structure/1BIC) — incl. mutant structure 12CA.

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

*Describes the biological roles of CA2 (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:** CA2's established molecular role includes arylesterase activity.


### Pathways affected {#pathways}

CA2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Developmental Lineage of Pancreatic Ductal Cells](https://reactome.org/content/detail/R-HSA-9925563) | curated |
| [Erythrocytes take up carbon dioxide and release oxygen](https://reactome.org/content/detail/R-HSA-1237044) | curated |
| [Erythrocytes take up oxygen and release carbon dioxide](https://reactome.org/content/detail/R-HSA-1247673) | curated |
| [Reversible hydration of carbon dioxide](https://reactome.org/content/detail/R-HSA-1475029) | curated |

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

**Molecular function:** arylesterase activity, carbonate dehydratase activity, zinc ion binding.

**Biological process:** angiotensin-activated signaling pathway, regulation of monoatomic anion transport.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-06-16.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2020-06-16 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CA2 variant pages (same residue, condition, or type): [CA2 p.Lys227fs](/variant/ca2-p-lys227fs), [CA2 p.Lys224fs](/variant/ca2-p-lys224fs), [CA2 p.Gly63_His64del](/variant/ca2-p-gly63-his64del), [CA2 c.35-18_35-17del](/variant/ca2-c-35-minus-18-35-minus-17del), [CA2 c.351+19_351+21del](/variant/ca2-c-351-plus-19-351-plus-21del), [CA2 c.351+21del](/variant/ca2-c-351-plus-21del), [CA2 c.352-10del](/variant/ca2-c-352-minus-10del), [CA2 c.508-204del](/variant/ca2-c-508-minus-204del).

### 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 1227991). 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.*