# NM_033100.4(CDHR1):c.738C>T (p.Phe246=)

https://sugi.bio/variant/cdhr1-p-phe246

## Summary

**CDHR1 p.Phe246= (c.738C>T)** is classified **Likely benign** in CDHR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-08). Ultra-rare (popmax 0.0725%, sas).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs141693979 · 2 submitters · ultra-rare (popmax 0.0725%, 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 2 submitters.

*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.Phe246= |
| Coding change (HGVS c.) | c.738C>T |
| MANE Select transcript | [NM_033100](https://www.ncbi.nlm.nih.gov/nuccore/NM_033100) |
| dbSNP | [rs141693979](https://www.ncbi.nlm.nih.gov/snp/rs141693979/) |
| Variant type | single nucleotide variant |
| Location | chr10:84203078-84203078 (GRCh38) |
| ClinVar | [VCV1082318](https://www.ncbi.nlm.nih.gov/clinvar/variation/1082318/) |

**All HGVS expressions:** `NC_000010.10:g.85962834C>T`, `NC_000010.11:g.84203078C>T`, `NG_028034.1:g.13423C>T`, `NM_001171971.3:c.738C>T`, `NM_033100.4:c.738C>T`

## 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 -1.427, GERP -0.774 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 11.11**. 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 (C>G, Δ0.23 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 **0.0725%** (sas) · FAF95 0.0584% · FAF99 0.0533% · 66/91,088 in the highest group · 124/1,614,232 alleles overall — ultra-rare (popmax 0.0725%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.128% | 779 |
| South Asian (grpmax) | 0.0725% | 1,380 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,419 |
| African / African-American | 0.00533% | 18,766 |
| European (non-Finnish) | 0.000847% | 118,004 |

Ashkenazi Jewish 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 **246** lies in the cadherin 2 domain.

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

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-08.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-08 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-04 |

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

## Similar variants {#similar}

Related CDHR1 variant pages (same residue, condition, or type): [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), [CDHR1 c.525+1G>A](/variant/cdhr1-c-525-plus-1g-a), [CDHR1 c.526-1G>A](/variant/cdhr1-c-526-minus-1g-a).

### 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 1082318). 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.*