# NM_001739.2(CA5A):c.697T>C (p.Ser233Pro)

https://sugi.bio/variant/ca5a-p-ser233pro

## Summary

**CA5A p.Ser233Pro (c.697T>C)** is classified **Conflicting classifications of pathogenicity** in CA5A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2022-09-26). AlphaMissense: likely pathogenic (0.9477); Very rare (popmax 0.00404%, nfe); Associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs587777316 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00404%, nfe)

## 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 4 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.Ser233Pro |
| Coding change (HGVS c.) | c.697T>C |
| MANE Select transcript | [NM_001739](https://www.ncbi.nlm.nih.gov/nuccore/NM_001739) |
| dbSNP | [rs587777316](https://www.ncbi.nlm.nih.gov/snp/rs587777316/) |
| Variant type | single nucleotide variant |
| Location | chr16:87891876-87891876 (GRCh38) |
| ClinVar | [VCV127087](https://www.ncbi.nlm.nih.gov/clinvar/variation/127087/) |

**All HGVS expressions:** `LRG_1280:g.49654T>C`, `LRG_1280t1:c.697T>C`, `NC_000016.10:g.87891876A>G`, `NC_000016.9:g.87925482A>G`, `NG_033227.2:g.49654T>C`, `NM_001367225.1:c.697T>C`, `NM_001739.2:c.697T>C`, `NR_159798.1:n.884T>C`, `NR_159799.1:n.657T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9477)
- REVEL 0.957 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.181 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 10.935, GERP 1.97, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in CA5A (of 1,776 modeled).
- CADD: **PHRED 25.1**. 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: **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 (gnomAD v4.1): grpmax **0.00404%** (nfe) · FAF95 0.00312% · FAF99 0.00279% · 47/1,162,196 in the highest group · 51/1,574,768 alleles overall — very rare (popmax 0.00404%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00404% | 24,728 |
| Finnish (not grpmax-eligible) | 0.00321% | 31,105 |
| Remaining individuals (not grpmax-eligible) | 0.00164% | 60,868 |
| South Asian | 0.00117% | 85,822 |

*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 **233** lies in the alpha-carbonic anhydrase domain; a UniProt-annotated variant site (in ca5ad; decreased carbonate dehydratase activity; decreased protein thermal stability).

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.Ser233Pro 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 2022-09-26.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely pathogenic, 1 Pathogenic, 1 not provided).

**Submission history:** 4 submissions (2014–2022); 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 | 2022-09-26 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-08-11 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2014-03-06 |
| GeneReviews | not provided | no classification provided | literature only |  |

## 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, not provided, Carbonic anhydrase VA deficiency, hyperammonemia due to, Carbonic Anhydrase VA Deficiency, none provided.

## Similar variants {#similar}

Related CA5A variant pages (same residue, condition, or type): [CA5A p.Ser233=](/variant/ca5a-p-ser233), [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 2026-10-14); 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 127087). 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.*