# NM_033100.4(CDHR1):c.476_477inv (p.Ala159Val)

https://sugi.bio/variant/cdhr1-p-ala159val

## Summary

**CDHR1 p.Ala159Val (c.476_477inv)** is classified **Uncertain significance** in CDHR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-13).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the CDHR1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Ala159Val |
| Coding change (HGVS c.) | c.476_477inv |
| MANE Select transcript | [NM_033100](https://www.ncbi.nlm.nih.gov/nuccore/NM_033100) |
| Variant type | Inversion |
| Location | chr10:84200638-84200639 (GRCh38) |
| ClinVar | [VCV1061875](https://www.ncbi.nlm.nih.gov/clinvar/variation/1061875/) |

**All HGVS expressions:** `NC_000010.10:g.85960394_85960395inv`, `NC_000010.11:g.84200638_84200639inv`, `NG_028034.1:g.10983_10984inv`, `NM_001171971.3:c.476_477inv`, `NM_033100.4:c.476_477inv`

## 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 7.576, GERP 4.47, phastCons 1 — highly conserved position (PP3-type support)
- Regional missense constraint: **o/e 1.06** across the covering region of the MANE Select transcript (84,194,761–84,214,618), spanning 19,857 bp. Chi-square p 0.035. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no inversion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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 **159** lies in the cadherin 2 domain.

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

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-13.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-13 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Same-residue context {#hotspot}

Residue **159** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CDHR1 p.Ala159Glu](/variant/cdhr1-p-ala159glu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CDHR1 variant pages (same residue, condition, or type): [CDHR1 p.Ala159=](/variant/cdhr1-p-ala159), [CDHR1 p.Ala159Glu](/variant/cdhr1-p-ala159glu).

### 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 1061875). 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.*