# NM_001739.2(CA5A):c.287G>C (p.Trp96Ser)

https://sugi.bio/variant/ca5a-p-trp96ser

## Summary

**CA5A p.Trp96Ser (c.287G>C)** is classified **Conflicting classifications of pathogenicity** in CA5A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-15). AlphaMissense: likely benign (0.2837); Very rare (popmax 0.008%, afr); Associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs766339583 · 4 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.008%, afr)

## 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.Trp96Ser |
| Coding change (HGVS c.) | c.287G>C |
| MANE Select transcript | [NM_001739](https://www.ncbi.nlm.nih.gov/nuccore/NM_001739) |
| dbSNP | [rs766339583](https://www.ncbi.nlm.nih.gov/snp/rs766339583/) |
| Variant type | single nucleotide variant |
| Location | chr16:87926801-87926801 (GRCh38) |
| ClinVar | [VCV1203736](https://www.ncbi.nlm.nih.gov/clinvar/variation/1203736/) |

**All HGVS expressions:** `LRG_1280:g.14729G>C`, `LRG_1280t1:c.287G>C`, `NC_000016.10:g.87926801C>G`, `NC_000016.9:g.87960407C>G`, `NG_033227.2:g.14729G>C`, `NM_001367225.1:c.287G>C`, `NM_001739.2:c.287G>C`, `NR_159798.1:n.366G>C`, `NR_159799.1:n.366G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2837)
- REVEL 0.405 (indeterminate)
- SaProt LLR -2.408 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 5.751, GERP 1.97, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.2**. 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 **0.008%** (afr) · FAF95 0.0041% · FAF99 0.00372% · 6/74,954 in the highest group · 84/1,614,118 alleles overall — very rare (popmax 0.008%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.024% | 4,166 |
| African / African-American (grpmax) | 0.008% | 12,492 |
| European (non-Finnish) | 0.00517% | 19,345 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,013 |

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}

**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 **96** 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.Trp96Ser 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 2025-08-15.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign).

**Submission history:** 4 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-15 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-31 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-13 |

## 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, Inborn genetic diseases, not specified, Carbonic Anhydrase VA Deficiency, Carbonic anhydrase VA deficiency, hyperammonemia due to, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related CA5A variant pages (same residue, condition, or type): [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), [CA5A p.Gln79Glu](/variant/ca5a-p-gln79glu).

### 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 1203736). 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.*