# NM_007220.4(CA5B):c.764A>C (p.Asp255Ala)

https://sugi.bio/variant/ca5b-p-asp255ala

## Summary

**CA5B p.Asp255Ala (c.764A>C)** is classified **Uncertain significance** in CA5B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.0972); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CA5B 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 | [CA5B](https://sugi.bio/atlas/gene/CA5B/) |
| Protein change (HGVS p.) | p.Asp255Ala |
| Coding change (HGVS c.) | c.764A>C |
| MANE Select transcript | [NM_007220](https://www.ncbi.nlm.nih.gov/nuccore/NM_007220) |
| Variant type | single nucleotide variant |
| Location | chrX:15776859-15776859 (GRCh38) |
| ClinVar | [VCV3483759](https://www.ncbi.nlm.nih.gov/clinvar/variation/3483759/) |

**All HGVS expressions:** `NC_000023.10:g.15794982A>C`, `NC_000023.11:g.15776859A>C`, `NG_012766.1:g.43571A>C`, `NM_007220.4:c.764A>C`, `NR_160544.1:n.2179A>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0972)
- REVEL 0.244 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.071 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.198, GERP 0.496, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 16.01**. 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 1.05** across the covering region of the MANE Select transcript (15,764,764–15,782,661), spanning 17,897 bp. Chi-square p 0.53. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>G, Δ0.30 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- 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.*

## Protein context {#protein}

Residue **255** lies in the alpha-carbonic anhydrase domain.

AlphaFold model confidence (whole protein): pLDDT 83.33, 74% of residues very-high.

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

*Describes the biological roles of CA5B (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:** CA5B's established molecular role includes carbonate dehydratase activity. p.Asp255Ala falls in the alpha-carbonic anhydrase domain.


### Pathways affected {#pathways}

CA5B 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}

**Molecular function:** carbonate dehydratase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-20 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CA5B variant pages (same residue, condition, or type): [CA5B p.Ala135Pro](/variant/ca5b-p-ala135pro), [CA5B p.Ala138Val](/variant/ca5b-p-ala138val), [CA5B p.Ala170Glu](/variant/ca5b-p-ala170glu), [CA5B p.Ala47Val](/variant/ca5b-p-ala47val), [CA5B p.Arg282Cys](/variant/ca5b-p-arg282cys), [CA5B p.Arg282His](/variant/ca5b-p-arg282his), [CA5B p.Arg290Leu](/variant/ca5b-p-arg290leu), [CA5B p.Arg293His](/variant/ca5b-p-arg293his).

### 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 3483759). 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.*