# NM_172351.3(CD46):c.202_203dup (p.Phe69fs)

https://sugi.bio/variant/cd46-p-phe69fs

## Summary

**CD46 p.Phe69fs (c.202_203dup)** is classified **Pathogenic** in CD46 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). Associated with atypical hemolytic-uremic syndrome.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CD46 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to atypical hemolytic-uremic syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Not applicable |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (United States) |
| Clinical trials | 40 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CD46 is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Atypical hemolytic uremic syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Proteinuria — Very frequent (99-80%)
- Hematuria — Very frequent (99-80%)
- Abnormality of blood and blood-forming tissues — Very frequent (99-80%)
- Thrombocytopenia — Very frequent (99-80%)
- Acute kidney injury — Very frequent (99-80%)
- Microangiopathic hemolytic anemia — Very frequent (99-80%)
- Abnormality of metabolism/homeostasis — Very frequent (99-80%)
- Abnormal lactate dehydrogenase activity — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008702/index) · [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.Phe69fs |
| Coding change (HGVS c.) | c.202_203dup |
| MANE Select transcript | [NM_172351](https://www.ncbi.nlm.nih.gov/nuccore/NM_172351) |
| Variant type | Duplication |
| Location | chr1:207757116-207757117 (GRCh38) |
| ClinVar | [VCV4291258](https://www.ncbi.nlm.nih.gov/clinvar/variation/4291258/) |

**All HGVS expressions:** `LRG_155:g.10062_10063dup`, `LRG_155t1:c.202_203dup`, `NC_000001.10:g.207930463_207930464dup`, `NC_000001.11:g.207757118_207757119dup`, `NG_009296.1:g.10062_10063dup`, `NM_002389.4:c.202_203dup`, `NM_153826.4:c.202_203dup`, `NM_172350.3:c.202_203dup`, `NM_172351.3:c.202_203dup`, `NM_172352.3:c.202_203dup`, `NM_172353.3:c.202_203dup`, `NM_172355.3:c.202_203dup`, `NM_172356.3:c.202_203dup`, `NM_172357.3:c.202_203dup`, `NM_172358.3:c.202_203dup`, `NM_172359.3:c.202_203dup`, `NM_172361.3:c.202_203dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 5.475, GERP 1.56, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.763, pLI 0.041886. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 13**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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 **69** lies in a disulfide bond; the sushi 1 domain; a β-strand.

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.Phe69fs 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-02.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomenon, Inc, Genomenon, Inc | Pathogenic | criteria provided, single submitter | curation | 2025-10-02 |

## Associated conditions {#conditions}

[atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/).

**Reported phenotype names (ClinVar):** Atypical hemolytic-uremic syndrome.

## Similar variants {#similar}

Related CD46 variant pages (same residue, condition, or type): [CD46 p.Glu118fs](/variant/cd46-p-glu118fs), [CD46 p.Asn235fs](/variant/cd46-p-asn235fs), [CD46 c.1082+2T>A](/variant/cd46-c-1082-plus-2t-a), [CD46 c.286+1G>C](/variant/cd46-c-286-plus-1g-c), [CD46 c.286+2T>G](/variant/cd46-c-286-plus-2t-g), [CD46 c.287-2A>G](/variant/cd46-c-287-minus-2a-g), [CD46 p.Arg229Ter](/variant/cd46-p-arg229ter), [CD46 p.Arg59Ter](/variant/cd46-p-arg59ter).

### 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 4291258). 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.*