# NM_201548.5(CERKL):c.783T>C (p.Pro261=)

https://sugi.bio/variant/cerkl-p-pro261

## Summary

**CERKL p.Pro261= (c.783T>C)** is classified **Conflicting classifications of pathogenicity** in CERKL (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-28). Rare (popmax 0.558%, afr); Associated with retinitis pigmentosa.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs77741297 · 7 submitters · 2 linked conditions · rare (popmax 0.558%, afr)

## For patients & families {#patients}

This is a change in the CERKL gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 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 |
| Diagnostic panels | CERKL is a diagnostic-grade gene on 1 Genomics England panel |

**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 | [CERKL](https://sugi.bio/atlas/gene/CERKL/) |
| Protein change (HGVS p.) | p.Pro261= |
| Coding change (HGVS c.) | c.783T>C |
| MANE Select transcript | [NM_201548](https://www.ncbi.nlm.nih.gov/nuccore/NM_201548) |
| dbSNP | [rs77741297](https://www.ncbi.nlm.nih.gov/snp/rs77741297/) |
| Variant type | single nucleotide variant |
| Location | chr2:181558603-181558603 (GRCh38) |
| ClinVar | [VCV897708](https://www.ncbi.nlm.nih.gov/clinvar/variation/897708/) |

**All HGVS expressions:** `NC_000002.11:g.182423330A>G`, `NC_000002.12:g.181558603A>G`, `NG_021178.2:g.103505T>C`, `NM_001030311.3:c.861T>C`, `NM_001030312.3:c.482-8895T>C`, `NM_001030313.3:c.614-8895T>C`, `NM_001160277.2:c.729T>C`, `NM_201548.5:c.783T>C`, `NR_027689.2:n.686T>C`, `NR_027690.2:n.818T>C`

## 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 -3.74, GERP -3.86 — fast-evolving / accelerated position
- CADD: **PHRED 0.281**. 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 (A>C, Δ0.59 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 **0.558%** (afr) · FAF95 0.514% · FAF99 0.497% · 419/75,024 in the highest group · 494/1,613,760 alleles overall — rare (popmax 0.558%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.558% | 179 |
| Middle Eastern | 0.0828% | 1,207 |
| Remaining individuals (not grpmax-eligible) | 0.0448% | 2,232 |
| Admixed American | 0.04% | 2,498 |
| South Asian | 0.00439% | 22,771 |
| European (non-Finnish) | 0.00119% | 84,272 |

*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}

**CERKL** population constraint: LOEUF 1.43, pLI 2.2725e-17, missense-Z -0.14752. *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):

- **CERKL-related retinopathy** — Definitive (AR)

## Protein context {#protein}

Residue **261** lies in the dagkc domain.

AlphaFold model confidence (whole protein): pLDDT 79.82, 58% of residues very-high.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-28.

**Submitter consensus:** conflicting (5 Likely benign, 1 Uncertain significance, 1 Benign).

**Submission history:** 7 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Clinical Genetics, Academic Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2020-06-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-14 |

## Associated conditions {#conditions}

[retinitis pigmentosa](https://sugi.bio/atlas/disease/retinitis-pigmentosa/), [retinitis pigmentosa 26](https://sugi.bio/atlas/disease/retinitis-pigmentosa-26/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa, Retinitis pigmentosa 26, not provided, not specified, none provided, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **261** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CERKL p.Pro261fs](/variant/cerkl-p-pro261fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CERKL variant pages (same residue, condition, or type): [CERKL p.Pro261fs](/variant/cerkl-p-pro261fs), [CERKL p.Pro261Arg](/variant/cerkl-p-pro261arg), [CERKL c.1074-1G>C](/variant/cerkl-c-1074-minus-1g-c), [CERKL c.1074-2A>C](/variant/cerkl-c-1074-minus-2a-c), [CERKL c.1074-2A>G](/variant/cerkl-c-1074-minus-2a-g), [CERKL c.1365+1G>A](/variant/cerkl-c-1365-plus-1g-a), [CERKL c.1366-1G>A](/variant/cerkl-c-1366-minus-1g-a), [CERKL c.1366-1G>T](/variant/cerkl-c-1366-minus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 897708). 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.*