# NM_000717.5(CA4):c.699C>T (p.Val233=)

https://sugi.bio/variant/ca4-p-val233

## Summary

**CA4 p.Val233= (c.699C>T)** is classified **Conflicting classifications of pathogenicity** in CA4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2018-01-12). Very rare (popmax 0.00446%, eas); Associated with retinitis pigmentosa.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs764759588 · 2 submitters · 1 linked condition · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the CA4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to retinitis pigmentosa.

*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 dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 238 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of Retinitis pigmentosa** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Conductive hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Retinal degeneration — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005694/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CA4](https://sugi.bio/atlas/gene/CA4/) |
| Protein change (HGVS p.) | p.Val233= |
| Coding change (HGVS c.) | c.699C>T |
| MANE Select transcript | [NM_000717](https://www.ncbi.nlm.nih.gov/nuccore/NM_000717) |
| dbSNP | [rs764759588](https://www.ncbi.nlm.nih.gov/snp/rs764759588/) |
| Variant type | single nucleotide variant |
| Location | chr17:60158401-60158401 (GRCh38) |
| ClinVar | [VCV728481](https://www.ncbi.nlm.nih.gov/clinvar/variation/728481/) |

**All HGVS expressions:** `NC_000017.10:g.58235762C>T`, `NC_000017.11:g.60158401C>T`, `NG_012050.2:g.13461C>T`, `NM_000717.5:c.699C>T`, `NR_137422.2:n.761C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -3.505, GERP -4.25 — fast-evolving / accelerated position
- CADD: **PHRED 0.442**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.95 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 (gnomAD v4.1): grpmax **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000276% · 2/44,876 in the highest group · 14/1,461,814 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,438 |
| South Asian | 0.0022% | 45,535 |
| Admixed American | 0.00167% | 60,020 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,506 |
| European (non-Finnish) | 0.000678% | 147,503 |

*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}

**CA4** population constraint: LOEUF 0.975, pLI 1.3264e-06, missense-Z 0.13739. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **233** lies in the alpha-carbonic anhydrase domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 89.86, 81% of residues very-high.

**10 experimental structure(s)** (PDB): [1ZNC](https://www.rcsb.org/structure/1ZNC), [3F7B](https://www.rcsb.org/structure/3F7B), [3F7U](https://www.rcsb.org/structure/3F7U), [3FW3](https://www.rcsb.org/structure/3FW3), [5IPZ](https://www.rcsb.org/structure/5IPZ), [5JN8](https://www.rcsb.org/structure/5JN8).

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

*Describes the biological roles of CA4 (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.*


### Pathways affected {#pathways}

CA4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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}

**Biological process:** bicarbonate transport.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2018-01-12.

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

**Submission history:** 2 submissions (2017–2018); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2017-11-28 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |

## Associated conditions {#conditions}

[retinitis pigmentosa](https://sugi.bio/atlas/disease/retinitis-pigmentosa/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa, not provided, none provided.

## Similar variants {#similar}

Related CA4 variant pages (same residue, condition, or type): [CA4 p.Val233Leu](/variant/ca4-p-val233leu), [CA4 p.Ile54Met](/variant/ca4-p-ile54met), [CA4 p.Phe70Leu](/variant/ca4-p-phe70leu), [CA4 c.-24G>C](/variant/ca4-c-minus-24g-c), [CA4 c.-47C>G](/variant/ca4-c-minus-47c-g), [CA4 p.Arg239Gln](/variant/ca4-p-arg239gln), [CA4 p.Asn177Lys](/variant/ca4-p-asn177lys), [CA4 p.Asn269=](/variant/ca4-p-asn269).

### 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 728481). 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.*