# NM_001739.2(CA5A):c.788G>A (p.Arg263His)

https://sugi.bio/variant/ca5a-p-arg263his

## Summary

**CA5A p.Arg263His (c.788G>A)** is classified **Conflicting classifications of pathogenicity** in CA5A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.2281); Rare (popmax 0.998%, sas); Associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs201195769 · 2 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.998%, sas)

## For patients & families {#patients}

This is a change in the CA5A gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

*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) | Childhood, Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CA5A is a diagnostic-grade gene on 10 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013201/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CA5A](https://sugi.bio/atlas/gene/CA5A/) |
| Protein change (HGVS p.) | p.Arg263His |
| Coding change (HGVS c.) | c.788G>A |
| MANE Select transcript | [NM_001739](https://www.ncbi.nlm.nih.gov/nuccore/NM_001739) |
| dbSNP | [rs201195769](https://www.ncbi.nlm.nih.gov/snp/rs201195769/) |
| Variant type | single nucleotide variant |
| Location | chr16:87888259-87888259 (GRCh38) |
| ClinVar | [VCV1652614](https://www.ncbi.nlm.nih.gov/clinvar/variation/1652614/) |

**All HGVS expressions:** `LRG_1280:g.53271G>A`, `LRG_1280t1:c.788G>A`, `NC_000016.10:g.87888259C>T`, `NC_000016.9:g.87921865C>T`, `NG_033227.2:g.53271G>A`, `NM_001367225.1:c.774+3540G>A`, `NM_001739.2:c.788G>A`, `NR_159798.1:n.975G>A`, `NR_159799.1:n.748G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2281)
- REVEL 0.738 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -12.079 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 7.508, GERP 1.68, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.7**. 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 1.11** across the covering region of the MANE Select transcript (87,888,132–87,936,450), spanning 48,318 bp. Chi-square p 0.027. 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 (C>A, Δ0.26 acceptor 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 (gnomAD v4.1): grpmax **0.998%** (sas) · FAF95 0.944% · FAF99 0.923% · 908/90,976 in the highest group · 989/1,613,076 alleles overall — rare (popmax 0.998%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.998% | 100 |
| Middle Eastern | 0.0992% | 1,008 |
| Remaining individuals (not grpmax-eligible) | 0.048% | 2,082 |
| Admixed American | 0.0184% | 5,449 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0101% | 9,857 |
| African / African-American | 0.00267% | 37,477 |
| European (non-Finnish) | 0.00246% | 40,667 |

*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}

**CA5A** population constraint: LOEUF 1.257, pLI 1.8303e-07, missense-Z -1.3698. *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):

- **hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **263** lies in the alpha-carbonic anhydrase domain.

AlphaFold model confidence (whole protein): pLDDT 84.38, 76% of residues very-high.

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

*Describes the biological roles of CA5A (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:** CA5A's established molecular role includes carbonate dehydratase activity. p.Arg263His falls in the alpha-carbonic anhydrase domain.


### Pathways affected {#pathways}

CA5A 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-01.

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

**Submission history:** 2 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-01 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-03-28 |

## Associated conditions {#conditions}

[hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency](https://sugi.bio/atlas/disease/hyperammonemic-encephalopathy-due-to-carbonic-anhydrase-va-deficiency/).

**Reported phenotype names (ClinVar):** Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency, Carbonic anhydrase VA deficiency, hyperammonemia due to, Carbonic Anhydrase VA Deficiency.

## Similar variants {#similar}

Related CA5A variant pages (same residue, condition, or type): [CA5A p.Arg263Cys](/variant/ca5a-p-arg263cys), [CA5A p.Arg32Ter](/variant/ca5a-p-arg32ter), [CA5A p.Glu241Lys](/variant/ca5a-p-glu241lys), [CA5A p.Ala149Thr](/variant/ca5a-p-ala149thr), [CA5A p.Ala208Val](/variant/ca5a-p-ala208val), [CA5A p.Ala261Val](/variant/ca5a-p-ala261val), [CA5A p.Arg26His](/variant/ca5a-p-arg26his), [CA5A p.Asp216Ala](/variant/ca5a-p-asp216ala).

### 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 1652614). 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.*