# NM_033100.4(CDHR1):c.823C>A (p.Arg275=)

https://sugi.bio/variant/cdhr1-p-arg275

## Summary

**CDHR1 p.Arg275= (c.823C>A)** is classified **Likely benign** in CDHR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). Very rare (popmax 0.00329%, sas).

**At a glance:** Likely benign · review: Single submitter · rsID rs200640039 · 1 submitter · very rare (popmax 0.00329%, sas)

## For patients & families {#patients}

This is a change in the CDHR1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [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.Arg275= |
| Coding change (HGVS c.) | c.823C>A |
| MANE Select transcript | [NM_033100](https://www.ncbi.nlm.nih.gov/nuccore/NM_033100) |
| dbSNP | [rs200640039](https://www.ncbi.nlm.nih.gov/snp/rs200640039/) |
| Variant type | single nucleotide variant |
| Location | chr10:84204566-84204566 (GRCh38) |
| ClinVar | [VCV1080092](https://www.ncbi.nlm.nih.gov/clinvar/variation/1080092/) |

**All HGVS expressions:** `NC_000010.10:g.85964322C>A`, `NC_000010.11:g.84204566C>A`, `NG_028034.1:g.14911C>A`, `NM_001171971.3:c.823C>A`, `NM_033100.4:c.823C>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 **acceptor loss** (Δ 0.26) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.396, GERP 2.71, phastCons 0.309 — weakly conserved position
- CADD: **PHRED 8.824**. 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 **0.26**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 39 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.22** (loss), gain 0.00 / loss 0.22. 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 **0.00329%** (sas) · FAF95 0.000875% · FAF99 0.000443% · 3/91,060 in the highest group · 4/1,461,544 alleles overall — very rare (popmax 0.00329%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00329% | 30,353 |
| Admixed American | 0.00167% | 60,006 |

*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 **275** lies in the cadherin 3 domain.

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

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-09.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-08-09 |

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

## Similar variants {#similar}

Related CDHR1 variant pages (same residue, condition, or type): [CDHR1 p.Arg275Gln](/variant/cdhr1-p-arg275gln), [CDHR1 p.Arg275Trp](/variant/cdhr1-p-arg275trp), [CDHR1 c.1168-1G>C](/variant/cdhr1-c-1168-minus-1g-c), [CDHR1 c.1321-1G>A](/variant/cdhr1-c-1321-minus-1g-a), [CDHR1 c.1485+2T>C](/variant/cdhr1-c-1485-plus-2t-c), [CDHR1 c.1485+2T>G](/variant/cdhr1-c-1485-plus-2t-g), [CDHR1 c.1554-2A>C](/variant/cdhr1-c-1554-minus-2a-c), [CDHR1 c.297+1G>T](/variant/cdhr1-c-297-plus-1g-t).

### 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 1080092). 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.*