# NM_000611.6(CD59):c.286_295del (p.Phe96fs)

https://sugi.bio/variant/cd59-p-phe96fs

## Summary

**CD59 p.Phe96fs (c.286_295del)** is classified **Uncertain significance** in CD59 (ClinVar, Single submitter, 1 submitter). No gnomAD frequency available for this variant; Associated with primary CD59 deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2495426631 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CD59 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to primary CD59 deficiency.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | CD59 is a diagnostic-grade gene on 6 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017054/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD59](https://sugi.bio/atlas/gene/CD59/) |
| Protein change (HGVS p.) | p.Phe96fs |
| Coding change (HGVS c.) | c.286_295del |
| MANE Select transcript | [NM_000611](https://www.ncbi.nlm.nih.gov/nuccore/NM_000611) |
| dbSNP | [rs2495426631](https://www.ncbi.nlm.nih.gov/snp/rs2495426631/) |
| Variant type | Deletion |
| Location | chr11:33710218-33710227 (GRCh38) |
| ClinVar | [VCV2585022](https://www.ncbi.nlm.nih.gov/clinvar/variation/2585022/) |

**All HGVS expressions:** `LRG_41:g.31252_31261del`, `LRG_41t1:c.286_295del`, `NC_000011.10:g.33710221_33710230del`, `NC_000011.9:g.33731767_33731776del`, `NG_008057.1:g.31252_31261del`, `NM_000611.6:c.286_295del`, `NM_001127223.1:c.286_295del`, `NM_001127225.2:c.286_295del`, `NM_001127226.2:c.286_295del`, `NM_001127227.2:c.286_295del`, `NM_203329.3:c.286_295del`, `NM_203330.2:c.286_295del`, `NM_203331.3:c.286_295del`

## 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 -4.95, GERP -1.89 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.277, pLI 0.56556. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (4 of 4)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CD59** population constraint: LOEUF 1.277, pLI 0.56556, missense-Z 0.49864; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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 **96** lies in the upar/ly6 domain.

AlphaFold model confidence (whole protein): pLDDT 80.15, 54% of residues very-high.

**17 experimental structure(s)** (PDB): [1CDQ](https://www.rcsb.org/structure/1CDQ), [1CDR](https://www.rcsb.org/structure/1CDR), [1CDS](https://www.rcsb.org/structure/1CDS), [1ERG](https://www.rcsb.org/structure/1ERG), [1ERH](https://www.rcsb.org/structure/1ERH), [2J8B](https://www.rcsb.org/structure/2J8B) — incl. mutant structure 4BIK.

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

*Describes the biological roles of CD59 (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:** CD59's established molecular role includes protein sequestering activity. p.Phe96fs falls in the upar/ly6 domain.


### Pathways affected {#pathways}

CD59 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [COPII-mediated vesicle transport](https://reactome.org/content/detail/R-HSA-204005) | curated |
| [Cargo concentration in the ER](https://reactome.org/content/detail/R-HSA-5694530) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Molecular function:** protein sequestering activity.

**Biological process:** negative regulation of activation of membrane attack complex, regulation of complement activation, negative regulation of complement activation, regulation of complement-dependent cytotoxicity, negative regulation of complement-dependent cytotoxicity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Uncertain significance | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[primary CD59 deficiency](https://sugi.bio/atlas/disease/primary-cd59-deficiency/).

**Reported phenotype names (ClinVar):** Primary CD59 deficiency, CD59-mediated hemolytic anemia with or without immune-mediated polyneuropathy, HEMOLYTIC ANEMIA, CD59-MEDIATED.

## Similar variants {#similar}

Related CD59 variant pages (same residue, condition, or type): [CD59 p.Asp47_Phe48insTer](/variant/cd59-p-asp47-phe48inster), [CD59 p.Cys64fs](/variant/cd59-p-cys64fs), [CD59 p.Glu101fs](/variant/cd59-p-glu101fs), [CD59 p.Leu93_Cys94insTer](/variant/cd59-p-leu93-cys94inster), [CD59 p.Phe96Leu](/variant/cd59-p-phe96leu), [CD59 p.Phe96=](/variant/cd59-p-phe96), [CD59 p.Asp49fs](/variant/cd59-p-asp49fs), [CD59 p.Val42fs](/variant/cd59-p-val42fs).

### 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 2585022). 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.*