# NM_000717.5(CA4):c.681G>A (p.Pro227=)

https://sugi.bio/variant/ca4-p-pro227

## Summary

**CA4 p.Pro227= (c.681G>A)** is classified **Conflicting classifications of pathogenicity** in CA4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0761%, afr); Associated with retinitis pigmentosa.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs144467811 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0761%, afr)

## 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 3 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.Pro227= |
| Coding change (HGVS c.) | c.681G>A |
| MANE Select transcript | [NM_000717](https://www.ncbi.nlm.nih.gov/nuccore/NM_000717) |
| dbSNP | [rs144467811](https://www.ncbi.nlm.nih.gov/snp/rs144467811/) |
| Variant type | single nucleotide variant |
| Location | chr17:60158383-60158383 (GRCh38) |
| ClinVar | [VCV324235](https://www.ncbi.nlm.nih.gov/clinvar/variation/324235/) |

**All HGVS expressions:** `NC_000017.10:g.58235744G>A`, `NC_000017.11:g.60158383G>A`, `NG_012050.2:g.13443G>A`, `NM_000717.5:c.681G>A`, `NR_137422.2:n.743G>A`

## 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 -12.111, GERP -4.25 — fast-evolving / accelerated position
- CADD: **PHRED 0.02**. 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: **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 **0.0761%** (afr) · FAF95 0.0602% · FAF99 0.0545% · 57/74,916 in the highest group · 76/1,614,016 alleles overall — ultra-rare (popmax 0.0761%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0761% | 1,314 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,497 |
| Admixed American | 0.005% | 19,997 |
| South Asian | 0.00329% | 30,359 |
| European (non-Finnish) | 0.000678% | 147,504 |

*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 **227** lies in a disulfide bond; the alpha-carbonic anhydrase domain.

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 2025-12-03.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-11-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-03 |
| 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, not specified, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related CA4 variant pages (same residue, condition, or type): [CA4 p.Pro227Arg](/variant/ca4-p-pro227arg), [CA4 p.Pro227Leu](/variant/ca4-p-pro227leu), [CA4 p.Pro227Gln](/variant/ca4-p-pro227gln), [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).

### 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 324235). 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.*