# NM_000067.3(CA2):c.34G>A (p.Gly12Arg)

https://sugi.bio/variant/ca2-p-gly12arg

## Summary

**CA2 p.Gly12Arg (c.34G>A)** is classified **Uncertain significance** in CA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). AlphaMissense: likely pathogenic (0.9521); Very rare (popmax 0.0012%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.0012%, sas)

## For patients & families {#patients}

This is a change in the CA2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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/) |
| Protein change (HGVS p.) | p.Gly12Arg |
| Coding change (HGVS c.) | c.34G>A |
| MANE Select transcript | [NM_000067](https://www.ncbi.nlm.nih.gov/nuccore/NM_000067) |
| Variant type | single nucleotide variant |
| Location | chr8:85464115-85464115 (GRCh38) |
| ClinVar | [VCV4713838](https://www.ncbi.nlm.nih.gov/clinvar/variation/4713838/) |

**All HGVS expressions:** `NC_000008.10:g.86376344G>A`, `NC_000008.11:g.85464115G>A`, `NG_007287.1:g.5099G>A`, `NG_114630.1:g.100G>A`, `NG_114630.2:g.213G>A`, `NM_000067.3:c.34G>A`, `NM_001293675.2:c.-151G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9521)
- REVEL 0.922 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.882 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor gain** (Δ 0.39) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 10.971, GERP 1.64, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in CA2 (of 1,539 modeled).
- CADD: **PHRED 36.0**. 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.*
- Regional missense constraint: **o/e 0.92** across the covering region of the MANE Select transcript (85,464,082–85,473,796), spanning 9,714 bp. Chi-square p 0.33. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.07**, acceptor gain **0.00**, donor gain **0.39**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.07**, acceptor gain **0.00**, donor gain **0.39**.
- Pangolin: Δ**0.25** (loss), gain 0.23 / loss 0.25. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0012%** (sas) · 1/83,396 in the highest group · 1/1,389,848 alleles overall — very rare (popmax 0.0012%, sas).

*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 **12** lies in the alpha-carbonic anhydrase domain.

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.Gly12Arg 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-26.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-26 |

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

## Similar variants {#similar}

Related CA2 variant pages (same residue, condition, or type): [CA2 p.Gly12Glu](/variant/ca2-p-gly12glu), [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.Tyr193Ter](/variant/ca2-p-tyr193ter), [CA2 p.Arg181Cys](/variant/ca2-p-arg181cys), [CA2 p.Arg181His](/variant/ca2-p-arg181his), [CA2 p.Arg226His](/variant/ca2-p-arg226his).

### 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 4713838). 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.*