# NM_033100.4(CDHR1):c.783G>A (p.Pro261=)

https://sugi.bio/variant/cdhr1-p-pro261

## Summary

**CDHR1 p.Pro261= (c.783G>A)** is classified **Conflicting classifications of pathogenicity** in CDHR1 (ClinVar, Conflicting submitters, 25 submitters; last evaluated 2026-05-15). Rare (popmax 0.27%, nfe); Associated with inherited retinal dystrophy.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs147346345 · 25 submitters · 7 linked conditions · rare (popmax 0.27%, nfe)

## For patients & families {#patients}

This is a change in the CDHR1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 25 submitters, and is linked to inherited retinal dystrophy.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 40 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018916/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDHR1](https://sugi.bio/atlas/gene/CDHR1/) |
| Protein change (HGVS p.) | p.Pro261= |
| Coding change (HGVS c.) | c.783G>A |
| MANE Select transcript | [NM_033100](https://www.ncbi.nlm.nih.gov/nuccore/NM_033100) |
| dbSNP | [rs147346345](https://www.ncbi.nlm.nih.gov/snp/rs147346345/) |
| Variant type | single nucleotide variant |
| Location | chr10:84203123-84203123 (GRCh38) |
| ClinVar | [VCV301224](https://www.ncbi.nlm.nih.gov/clinvar/variation/301224/) |

**All HGVS expressions:** `NC_000010.10:g.85962879G>A`, `NC_000010.11:g.84203123G>A`, `NG_028034.1:g.13468G>A`, `NM_001171971.3:c.783G>A`, `NM_033100.4:c.783G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.68) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.455, GERP 2.62, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.1**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.68**, acceptor gain **0.00**, donor gain **0.04**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.68**, acceptor gain **0.00**, donor gain **0.04**.
- Pangolin: Δ**0.55** (loss), gain 0.26 / loss 0.55. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.27%** (nfe) · FAF95 0.263% · FAF99 0.259% · 3,191/1,180,036 in the highest group · 3,821/1,614,180 alleles overall — rare (popmax 0.27%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.564% | 177 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.348% | 287 |
| Amish (not grpmax-eligible) | 0.329% | 304 |
| European (non-Finnish) (grpmax) | 0.27% | 370 |
| Remaining individuals (not grpmax-eligible) | 0.187% | 534 |
| Admixed American | 0.0366% | 2,729 |
| African / African-American | 0.0187% | 5,360 |
| South Asian | 0.00988% | 10,120 |
| East Asian | 0.00223% | 44,872 |

Finnish 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}

**CDHR1** population constraint: LOEUF 1.004, pLI 1.0861e-16, missense-Z -0.43308; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **retinitis pigmentosa 65** — Definitive (AR)

## Protein context {#protein}

Residue **261** lies in the cadherin 3 domain.

AlphaFold model confidence (whole protein): pLDDT 78.79, 46% of residues very-high.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-05-15.

**Submitter consensus:** conflicting (13 Likely pathogenic, 9 Uncertain significance, 6 Pathogenic).

**Submission history:** 39 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Likely pathogenic | no assertion criteria provided | research | 2018-04-01 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-12-19 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-12-04 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-12-27 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Likely pathogenic | criteria provided, single submitter | curation | 2021-04-01 |
| Institute of Human Genetics, University of Leipzig Medical Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-12-08 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Uncertain significance | criteria provided, single submitter | curation | 2022-05-04 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2014-01-01 |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-10-23 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | research | 2023-04-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-01-26 |
| Institute of Human Genetics Munich, TUM University Hospital | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-08-14 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-27 |
| Mendelics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Institute of Medical Molecular Genetics, University of Zurich | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-01-30 |
| Molecular Genetics, Royal Melbourne Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-11 |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-01-01 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-09-11 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-30 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-10-27 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-15 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-01-07 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-28 |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-05-15 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-01 |

## Associated conditions {#conditions}

[inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/), [optic atrophy](https://sugi.bio/atlas/disease/optic-atrophy/), [retinal disorder](https://sugi.bio/atlas/disease/retinal-disorder/), [cone-rod dystrophy 15](https://sugi.bio/atlas/disease/cone-rod-dystrophy-15/), [retinitis pigmentosa](https://sugi.bio/atlas/disease/retinitis-pigmentosa/), [macular dystrophy, retinal, 5](https://sugi.bio/atlas/disease/macular-dystrophy-retinal-5/), [retinitis pigmentosa 65](https://sugi.bio/atlas/disease/retinitis-pigmentosa-65/).

**Reported phenotype names (ClinVar):** Retinal dystrophy, not provided, Cone-rod dystrophy 15, not specified, Retinitis pigmentosa, Retinitis pigmentosa 65, Macular dystrophy, retinal, 5, CDHR1-related disorder, Optic atrophy, Malignant tumor of urinary bladder.

## Same-residue context {#hotspot}

Residue **261** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CDHR1 p.Pro261fs](/variant/cdhr1-p-pro261fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CDHR1 variant pages (same residue, condition, or type): [CDHR1 p.Pro261Leu](/variant/cdhr1-p-pro261leu), [CDHR1 p.Pro261Ser](/variant/cdhr1-p-pro261ser), [CDHR1 c.1485+2T>G](/variant/cdhr1-c-1485-plus-2t-g), [CDHR1 c.525+1G>A](/variant/cdhr1-c-525-plus-1g-a), [CDHR1 c.56-1G>A](/variant/cdhr1-c-56-minus-1g-a), [CDHR1 c.863-1G>A](/variant/cdhr1-c-863-minus-1g-a), [CDHR1 p.Arg407Ter](/variant/cdhr1-p-arg407ter), [CDHR1 p.Tyr509Ter](/variant/cdhr1-p-tyr509ter).

### 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 301224). 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.*