# NM_021924.5(CDHR5):c.2263C>T (p.Pro755Ser)

https://sugi.bio/variant/cdhr5-p-pro755ser

## Summary

**CDHR5 p.Pro755Ser (c.2263C>T)** is classified **Uncertain significance** in CDHR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-05). AlphaMissense: likely benign (0.0734); Very rare (popmax 0.00137%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1485037364 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00137%, nfe)

## For patients & families {#patients}

This is a change in the CDHR5 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 | [CDHR5](https://sugi.bio/atlas/gene/CDHR5/) |
| Protein change (HGVS p.) | p.Pro755Ser |
| Coding change (HGVS c.) | c.2263C>T |
| MANE Select transcript | [NM_021924](https://www.ncbi.nlm.nih.gov/nuccore/NM_021924) |
| dbSNP | [rs1485037364](https://www.ncbi.nlm.nih.gov/snp/rs1485037364/) |
| Variant type | single nucleotide variant |
| Location | chr11:617626-617626 (GRCh38) |
| ClinVar | [VCV2543993](https://www.ncbi.nlm.nih.gov/clinvar/variation/2543993/) |

**All HGVS expressions:** `LRG_1313:g.3374C>T`, `NC_000011.10:g.617626G>A`, `NC_000011.9:g.617626G>A`, `NG_029106.1:g.3374C>T`, `NM_001171968.3:c.2245C>T`, `NM_021924.5:c.2263C>T`, `NM_031264.5:c.1681C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0734)
- REVEL 0.051 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.514 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.062, GERP -2.73 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.649**. 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.*
- Regional missense constraint: **o/e 1.11** across the covering region of the MANE Select transcript (617,354–624,902), spanning 7,548 bp. Chi-square p 0.00028. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.25 acceptor 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 **0.00137%** (nfe) · FAF95 0.000811% · FAF99 0.000656% · 16/1,168,260 in the highest group · 18/1,588,474 alleles overall — very rare (popmax 0.00137%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00326% | 30,708 |
| European (non-Finnish) (grpmax) | 0.00137% | 73,016 |

Remaining individuals 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}

**CDHR5** population constraint: LOEUF 1.479, pLI 9.8543e-33, missense-Z -1.6126. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **755** lies in the 'mediates interaction with ush1c and myo7b and is required for proper localization to microvilli tips and function in microvilli organization' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 69.84, 44% of residues very-high.

**1 experimental structure(s)** (PDB): [6OAE](https://www.rcsb.org/structure/6OAE).

## What this gene does {#gene-function}

*Describes the biological roles of CDHR5 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CDHR5's established molecular role includes beta-catenin binding. p.Pro755Ser falls in the mediates interaction with ush1c and myo7b and is required for proper localization to microvilli tips and function in microvilli organization region.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** beta-catenin binding, cell adhesion molecule binding.

**Biological process:** regulation of microvillus length, intermicrovillar adhesion, brush border assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-05 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CDHR5 variant pages (same residue, condition, or type): [CDHR5 p.Arg182His](/variant/cdhr5-p-arg182his), [CDHR5 p.Gly298=](/variant/cdhr5-p-gly298), [CDHR5 p.Ala151Pro](/variant/cdhr5-p-ala151pro), [CDHR5 p.Ala171Thr](/variant/cdhr5-p-ala171thr), [CDHR5 p.Ala230Thr](/variant/cdhr5-p-ala230thr), [CDHR5 p.Ala347Val](/variant/cdhr5-p-ala347val), [CDHR5 p.Ala364Val](/variant/cdhr5-p-ala364val), [CDHR5 p.Ala369Val](/variant/cdhr5-p-ala369val).

### 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 2543993). 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.*