# NM_000611.6(CD59):c.146A>T (p.Asp49Val)

https://sugi.bio/variant/cd59-p-asp49val

## Summary

**CD59 p.Asp49Val (c.146A>T)** is classified **Pathogenic** in CD59 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-15). AlphaMissense: likely pathogenic (0.9522); Very rare (popmax 8.48e-05%, nfe); Associated with primary CD59 deficiency.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the CD59 gene that is reported as disease-causing, but on limited review, 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.Asp49Val |
| Coding change (HGVS c.) | c.146A>T |
| MANE Select transcript | [NM_000611](https://www.ncbi.nlm.nih.gov/nuccore/NM_000611) |
| Variant type | single nucleotide variant |
| Location | chr11:33717393-33717393 (GRCh38) |
| ClinVar | [VCV4848546](https://www.ncbi.nlm.nih.gov/clinvar/variation/4848546/) |

**All HGVS expressions:** `LRG_41:g.24086A>T`, `LRG_41t1:c.146A>T`, `NC_000011.10:g.33717393T>A`, `NC_000011.9:g.33738939T>A`, `NG_008057.1:g.24086A>T`, `NM_000611.6:c.146A>T`, `NM_001127223.1:c.146A>T`, `NM_001127225.2:c.146A>T`, `NM_001127226.2:c.146A>T`, `NM_001127227.2:c.146A>T`, `NM_203329.3:c.146A>T`, `NM_203330.2:c.146A>T`, `NM_203331.3:c.146A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9522) — concordant with the pathogenic call
- REVEL 0.703 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.913 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.101, GERP 1.72, phastCons 0.975 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 9%** most-pathogenic-predicted substitutions in CD59 (of 746 modeled).
- CADD: **PHRED 23.2**. 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 0.95** across the covering region of the MANE Select transcript (33,710,129–33,722,445), spanning 12,316 bp. Chi-square p 0.52. 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 (T>C, Δ0.34 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 **8.48e-05%** (nfe) · 1/1,179,156 in the highest group · 1/1,613,156 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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 **49** 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.Asp49Val 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-04-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-15 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **49** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CD59 p.Asp49fs](/variant/cd59-p-asp49fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CD59 variant pages (same residue, condition, or type): [CD59 p.Asp49fs](/variant/cd59-p-asp49fs), [CD59 p.Cys89Tyr](/variant/cd59-p-cys89tyr), [CD59 p.Met1Thr](/variant/cd59-p-met1thr), [CD59 p.Cys28Tyr](/variant/cd59-p-cys28tyr), [CD59 p.Cys64Gly](/variant/cd59-p-cys64gly), [CD59 p.Tyr29Asp](/variant/cd59-p-tyr29asp), [CD59 p.Asp47_Phe48insTer](/variant/cd59-p-asp47-phe48inster), [CD59 p.Cys64fs](/variant/cd59-p-cys64fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4848546). 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.*