# NM_000067.3(CA2):c.681del (p.Lys227fs)

https://sugi.bio/variant/ca2-p-lys227fs

## Summary

**CA2 p.Lys227fs (c.681del)** is classified **Pathogenic/Likely pathogenic** in CA2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0283%, amr); Associated with autosomal recessive osteopetrosis 3.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs779869368 · 5 submitters · 1 linked condition · ultra-rare (popmax 0.0283%, amr)

## For patients & families {#patients}

This is a change in the CA2 gene that is considered likely disease-causing, submitted by 5 submitters, and is linked to autosomal recessive osteopetrosis 3.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | CA2 is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Osteopetrosis with renal tubular acidosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal tubular acidosis — Very frequent (99-80%)
- Osteopetrosis — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Abnormality of the dentition — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)
- Cranial nerve compression — Frequent (79-30%)
- Abnormal facial shape — Frequent (79-30%)
- Proximal renal tubular acidosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004154/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CA2](https://sugi.bio/atlas/gene/CA2/) |
| Protein change (HGVS p.) | p.Lys227fs |
| Coding change (HGVS c.) | c.681del |
| MANE Select transcript | [NM_000067](https://www.ncbi.nlm.nih.gov/nuccore/NM_000067) |
| dbSNP | [rs779869368](https://www.ncbi.nlm.nih.gov/snp/rs779869368/) |
| Variant type | Deletion |
| Location | chr8:85480685-85480685 (GRCh38) |
| ClinVar | [VCV632527](https://www.ncbi.nlm.nih.gov/clinvar/variation/632527/) |

**All HGVS expressions:** `NC_000008.10:g.86392916del`, `NC_000008.11:g.85480687del`, `NG_007287.1:g.21671del`, `NM_000067.2:c.681del`, `NM_000067.3:c.681del`, `NM_001293675.2:c.378del`

## 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 -1.034, GERP -2.82 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.491, pLI 3.9499e-08. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (7 of 7)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 23.4**. 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: **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 **0.0283%** (amr) · FAF95 0.018% · FAF99 0.0147% · 17/59,982 in the highest group · 30/1,613,594 alleles overall — ultra-rare (popmax 0.0283%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0283% | 3,528 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,810 |
| European (non-Finnish) | 0.000424% | 235,911 |

*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}

Residue **227** lies in the alpha-carbonic anhydrase domain; a turn.

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. p.Lys227fs falls in the alpha-carbonic anhydrase domain.


### 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-23.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Likely pathogenic).

**Submission history:** 5 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-04-28 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-06-30 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-23 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-12-09 |

## Associated conditions {#conditions}

[autosomal recessive osteopetrosis 3](https://sugi.bio/atlas/disease/autosomal-recessive-osteopetrosis-3/).

**Reported phenotype names (ClinVar):** Osteopetrosis with renal tubular acidosis, not provided, CA2-related disorder, Autosomal recessive osteopetrosis 3, none provided, CA2-related condition.

## Similar variants {#similar}

Related CA2 variant pages (same residue, condition, or type): [CA2 p.Lys224fs](/variant/ca2-p-lys224fs), [CA2 p.Lys227=](/variant/ca2-p-lys227), [CA2 p.Trp208fs](/variant/ca2-p-trp208fs), [CA2 c.232+1G>A](/variant/ca2-c-232-plus-1g-a), [CA2 p.Gln92Pro](/variant/ca2-p-gln92pro), [CA2 p.Glu204Ter](/variant/ca2-p-glu204ter), [CA2 p.Leu211fs](/variant/ca2-p-leu211fs), [CA2 p.Tyr193Ter](/variant/ca2-p-tyr193ter).

### 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 632527). 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.*