# NM_000067.3(CA2):c.433A>G (p.Ile145Val)

https://sugi.bio/variant/ca2-p-ile145val

## Summary

**CA2 p.Ile145Val (c.433A>G)** is classified **Conflicting classifications of pathogenicity** in CA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-19). AlphaMissense: likely benign (0.0919); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs768827690 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the CA2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.Ile145Val |
| Coding change (HGVS c.) | c.433A>G |
| MANE Select transcript | [NM_000067](https://www.ncbi.nlm.nih.gov/nuccore/NM_000067) |
| dbSNP | [rs768827690](https://www.ncbi.nlm.nih.gov/snp/rs768827690/) |
| Variant type | single nucleotide variant |
| Location | chr8:85474405-85474405 (GRCh38) |
| ClinVar | [VCV1399500](https://www.ncbi.nlm.nih.gov/clinvar/variation/1399500/) |

**All HGVS expressions:** `NC_000008.10:g.86386634A>G`, `NC_000008.11:g.85474405A>G`, `NG_007287.1:g.15389A>G`, `NM_000067.2:c.433A>G`, `NM_000067.3:c.433A>G`, `NM_001293675.2:c.130A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0919)
- REVEL 0.217 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.905 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.30) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.307, GERP -3.67 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.49**. 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 1.07** across the covering region of the MANE Select transcript (85,474,362–85,480,786), spanning 6,424 bp. Chi-square p 0.35. 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 **0.30**, acceptor gain **0.00**, donor gain **0.04**. Largest is donor loss, 3 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/59,970 in the highest group · 7/1,612,596 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,813 |
| Admixed American (grpmax) | 0.00333% | 29,985 |
| South Asian | 0.0022% | 45,535 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **145** lies in 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.Ile145Val 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-01-19.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-12 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-19 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related CA2 variant pages (same residue, condition, or type): [CA2 p.Ile145Thr](/variant/ca2-p-ile145thr), [CA2 p.Arg181His](/variant/ca2-p-arg181his), [CA2 p.Arg226His](/variant/ca2-p-arg226his), [CA2 p.Asn67Asp](/variant/ca2-p-asn67asp), [CA2 p.Asp179Glu](/variant/ca2-p-asp179glu), [CA2 p.Gln53Glu](/variant/ca2-p-gln53glu), [CA2 p.Glu14Lys](/variant/ca2-p-glu14lys), [CA2 p.Glu233Lys](/variant/ca2-p-glu233lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1399500). 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.*