# NM_172351.3(CD46):c.244_245delinsGT (p.Arg82Val)

https://sugi.bio/variant/cd46-p-arg82val

## Summary

**CD46 p.Arg82Val (c.244_245delinsGT)** is classified **Uncertain significance** in CD46 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29).

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

## For patients & families {#patients}

This is a change in the CD46 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 | [CD46](https://sugi.bio/atlas/gene/CD46/) |
| Protein change (HGVS p.) | p.Arg82Val |
| Coding change (HGVS c.) | c.244_245delinsGT |
| MANE Select transcript | [NM_172351](https://www.ncbi.nlm.nih.gov/nuccore/NM_172351) |
| Variant type | Indel |
| Location | chr1:207757160-207757161 (GRCh38) |
| ClinVar | [VCV3729432](https://www.ncbi.nlm.nih.gov/clinvar/variation/3729432/) |

**All HGVS expressions:** `LRG_155:g.10104_10105delinsGT`, `LRG_155t1:c.244_245delinsGT`, `NC_000001.10:g.207930505_207930506delinsGT`, `NC_000001.11:g.207757160_207757161delinsGT`, `NG_009296.1:g.10104_10105delinsGT`, `NM_002389.4:c.244_245delinsGT`, `NM_153826.4:c.244_245delinsGT`, `NM_172350.3:c.244_245delinsGT`, `NM_172351.3:c.244_245delinsGT`, `NM_172352.3:c.244_245delinsGT`, `NM_172353.3:c.244_245delinsGT`, `NM_172355.3:c.244_245delinsGT`, `NM_172356.3:c.244_245delinsGT`, `NM_172357.3:c.244_245delinsGT`, `NM_172358.3:c.244_245delinsGT`, `NM_172359.3:c.244_245delinsGT`, `NM_172361.3:c.244_245delinsGT`

## 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 -14.841, GERP -3.12 — fast-evolving / accelerated position
- Regional missense constraint: **o/e 0.88** across the covering region of the MANE Select transcript (207,752,213–207,790,301), spanning 38,088 bp. Chi-square p 0.012. 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 indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **segmental_duplication** (chr1:207652063). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*

*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}

**CD46** population constraint: LOEUF 0.763, pLI 0.041886, missense-Z 0.75927. *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):

- **atypical hemolytic-uremic syndrome** — Definitive (SD)

## Protein context {#protein}

Residue **82** lies in the sushi 1 domain.

AlphaFold model confidence (whole protein): pLDDT 82.38, 66% of residues very-high.

**7 experimental structure(s)** (PDB): [1CKL](https://www.rcsb.org/structure/1CKL), [2O39](https://www.rcsb.org/structure/2O39), [3INB](https://www.rcsb.org/structure/3INB), [3L89](https://www.rcsb.org/structure/3L89), [3O8E](https://www.rcsb.org/structure/3O8E), [5FO8](https://www.rcsb.org/structure/5FO8).

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

*Describes the biological roles of CD46 (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:** CD46's established molecular role includes cadherin binding. p.Arg82Val falls in the sushi 1 domain.


### Pathways affected {#pathways}

CD46 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Molecular function:** cadherin binding.

**Biological process:** T cell mediated immunity, regulation of Notch signaling pathway, positive regulation of gene expression, negative regulation of gene expression, positive regulation of interleukin-10 production, obsolete sequestering of extracellular ligand from receptor.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-29.

**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 | 2025-01-29 |

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

## Similar variants {#similar}

Related CD46 variant pages (same residue, condition, or type): [CD46 p.Arg82Gln](/variant/cd46-p-arg82gln), [CD46 p.Arg82Trp](/variant/cd46-p-arg82trp), [CD46 c.476-6_476-5delinsG](/variant/cd46-c-476-minus-6-476-minus-5delinsg), [CD46 p.Ile71Val](/variant/cd46-p-ile71val), [CD46 p.Val187Leu](/variant/cd46-p-val187leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3729432). 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.*