# NM_001218.5(CA12):c.686del (p.Pro229fs)

https://sugi.bio/variant/ca12-p-pro229fs

## Summary

**CA12 p.Pro229fs (c.686del)** is classified **Likely pathogenic** in CA12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-27). Associated with isolated hyperchlorhidrosis.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CA12 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to isolated hyperchlorhidrosis.

*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 |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017984/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CA12](https://sugi.bio/atlas/gene/CA12/) |
| Protein change (HGVS p.) | p.Pro229fs |
| Coding change (HGVS c.) | c.686del |
| MANE Select transcript | [NM_001218](https://www.ncbi.nlm.nih.gov/nuccore/NM_001218) |
| Variant type | Deletion |
| Location | chr15:63340349-63340349 (GRCh38) |
| ClinVar | [VCV3893023](https://www.ncbi.nlm.nih.gov/clinvar/variation/3893023/) |

**All HGVS expressions:** `NC_000015.10:g.63340353del`, `NC_000015.9:g.63632552del`, `NG_028022.2:g.46818del`, `NM_001218.5:c.686del`, `NM_001293642.2:c.506del`, `NM_206925.3:c.686del`, `NR_135511.2:n.859del`

## 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 -0.663, GERP -4.21 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.968, pLI 3.3815e-08. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 11**, 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.

*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}

**CA12** population constraint: LOEUF 0.968, pLI 3.3815e-08, missense-Z 0.45595; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **229** lies in the alpha-carbonic anhydrase domain.

AlphaFold model confidence (whole protein): pLDDT 88.50, 77% of residues very-high.

**40 experimental structure(s)** (PDB): [1JCZ](https://www.rcsb.org/structure/1JCZ), [1JD0](https://www.rcsb.org/structure/1JD0), [4HT2](https://www.rcsb.org/structure/4HT2), [4KP5](https://www.rcsb.org/structure/4KP5), [4KP8](https://www.rcsb.org/structure/4KP8), [4Q0L](https://www.rcsb.org/structure/4Q0L).

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

*Describes the biological roles of CA12 (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.*


### Pathways affected {#pathways}

CA12 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Reversible hydration of carbon dioxide](https://reactome.org/content/detail/R-HSA-1475029) | curated |

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

**Biological process:** chloride ion homeostasis.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely pathogenic | criteria provided, single submitter | research | 2023-03-27 |

## Associated conditions {#conditions}

[isolated hyperchlorhidrosis](https://sugi.bio/atlas/disease/isolated-hyperchlorhidrosis/).

**Reported phenotype names (ClinVar):** Isolated hyperchlorhidrosis.

## Similar variants {#similar}

Related CA12 variant pages (same residue, condition, or type): [CA12 p.Phe76=](/variant/ca12-p-phe76), [CA12 p.Glu143Lys](/variant/ca12-p-glu143lys), [CA12 p.His121Gln](/variant/ca12-p-his121gln), [CA12 p.Thr287fs](/variant/ca12-p-thr287fs), [CA12 p.Tyr195Ter](/variant/ca12-p-tyr195ter), [CA12 p.Val319fs](/variant/ca12-p-val319fs), [CA12 c.908-1G>A](/variant/ca12-c-908-minus-1g-a), [CA12 p.Gly223Ala](/variant/ca12-p-gly223ala).

### 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 3893023). 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.*