# NM_020770.3(CGN):c.166C>T (p.Arg56Cys)

https://sugi.bio/variant/cgn-p-arg56cys

## Summary

**CGN p.Arg56Cys (c.166C>T)** is classified **Uncertain significance** in CGN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). Very rare (popmax 0.00333%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the CGN 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 | [CGN](https://sugi.bio/atlas/gene/CGN/) |
| Protein change (HGVS p.) | p.Arg56Cys |
| Coding change (HGVS c.) | c.166C>T |
| MANE Select transcript | [NM_020770](https://www.ncbi.nlm.nih.gov/nuccore/NM_020770) |
| Variant type | single nucleotide variant |
| Location | chr1:151518685-151518685 (GRCh38) |
| ClinVar | [VCV3491758](https://www.ncbi.nlm.nih.gov/clinvar/variation/3491758/) |

**All HGVS expressions:** `NC_000001.10:g.151491161C>T`, `NC_000001.11:g.151518685C>T`, `NM_020770.3:c.166C>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 4.855, GERP 2.22, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 30.0**. 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 0.97** across the covering region of the MANE Select transcript (151,518,520–151,534,108), spanning 15,588 bp. Chi-square p 0.38. 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 (C>A, Δ0.33 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 **0.00333%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/59,992 in the highest group · 5/1,613,984 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 29,996 |
| European (non-Finnish) | 0.000254% | 393,342 |

*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}

**CGN** population constraint: LOEUF 0.88, pLI 3.2167e-29, missense-Z 1.1618. *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 **56** lies in the 'head' region; the 'interaction with tjp1/zo1' region.

AlphaFold model confidence (whole protein): pLDDT 70.44, 39% of residues very-high.

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

*Describes the biological roles of CGN (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:** CGN's established molecular role includes cadherin binding. p.Arg56Cys falls in the head region.


### Pathways affected {#pathways}

CGN participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)](https://reactome.org/content/detail/R-HSA-2173791) | other |

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

**Molecular function:** cadherin binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-02.

**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 | 2024-12-02 |

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

## Similar variants {#similar}

Related CGN variant pages (same residue, condition, or type): [CGN p.Ala357=](/variant/cgn-p-ala357), [CGN p.Arg11Trp](/variant/cgn-p-arg11trp), [CGN p.Arg227Trp](/variant/cgn-p-arg227trp), [CGN p.Arg547Lys](/variant/cgn-p-arg547lys), [CGN p.Arg973Gln](/variant/cgn-p-arg973gln), [CGN p.Glu771Lys](/variant/cgn-p-glu771lys), [CGN p.Ile60=](/variant/cgn-p-ile60), [CGN p.Ala1035Thr](/variant/cgn-p-ala1035thr).

### 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 3491758). 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.*