# NM_000067.3(CA2):c.275A>C (p.Gln92Pro)

https://sugi.bio/variant/ca2-p-gln92pro

## Summary

**CA2 p.Gln92Pro (c.275A>C)** is classified **Likely pathogenic** in CA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.966); Absent from gnomAD v4.1; Associated with autosomal recessive osteopetrosis 3.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs1304160279 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CA2 gene that is considered likely disease-causing, submitted by 3 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.Gln92Pro |
| Coding change (HGVS c.) | c.275A>C |
| MANE Select transcript | [NM_000067](https://www.ncbi.nlm.nih.gov/nuccore/NM_000067) |
| dbSNP | [rs1304160279](https://www.ncbi.nlm.nih.gov/snp/rs1304160279/) |
| Variant type | single nucleotide variant |
| Location | chr8:85473735-85473735 (GRCh38) |
| ClinVar | [VCV973759](https://www.ncbi.nlm.nih.gov/clinvar/variation/973759/) |

**All HGVS expressions:** `NC_000008.10:g.86385964A>C`, `NC_000008.11:g.85473735A>C`, `NG_007287.1:g.14719A>C`, `NM_000067.3:c.275A>C`, `NM_001293675.2:c.49-589A>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.966) — concordant with the pathogenic call
- REVEL 0.932 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.331 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.205, GERP 1.84, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in CA2 (of 1,539 modeled).
- CADD: **PHRED 26.6**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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}

**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 **92** lies in a functional site (involved in the binding of some activators, including histamine and l-histidine); a UniProt-annotated variant site (in optb3; in czechoslovakia); the alpha-carbonic anhydrase domain; a β-strand.

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.Gln92Pro 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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** unanimous (3/3 Likely pathogenic).

**Submission history:** 3 submissions (2023–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-06-22 |
| Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| CeGaT Center for Human Genetics Tuebingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-02-01 |

## 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, none provided, Autosomal recessive osteopetrosis 3.

## Similar variants {#similar}

Related CA2 variant pages (same residue, condition, or type): [CA2 c.232+1G>A](/variant/ca2-c-232-plus-1g-a), [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), [CA2 p.Asn67Asp](/variant/ca2-p-asn67asp), [CA2 p.Glu14Lys](/variant/ca2-p-glu14lys).

### 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 973759). 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.*