# NM_000611.6(CD59):c.384C>A (p.Pro128=)

https://sugi.bio/variant/cd59-p-pro128

## Summary

**CD59 p.Pro128= (c.384C>A)** is classified **Likely benign** in CD59 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-04). Ultra-rare (popmax 0.0178%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs549099946 · 1 submitter · ultra-rare (popmax 0.0178%, eas)

## For patients & families {#patients}

This is a change in the CD59 gene that is classified as likely benign — not considered disease-causing, 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 | [CD59](https://sugi.bio/atlas/gene/CD59/) |
| Protein change (HGVS p.) | p.Pro128= |
| Coding change (HGVS c.) | c.384C>A |
| MANE Select transcript | [NM_000611](https://www.ncbi.nlm.nih.gov/nuccore/NM_000611) |
| dbSNP | [rs549099946](https://www.ncbi.nlm.nih.gov/snp/rs549099946/) |
| Variant type | single nucleotide variant |
| Location | chr11:33710129-33710129 (GRCh38) |
| ClinVar | [VCV1943798](https://www.ncbi.nlm.nih.gov/clinvar/variation/1943798/) |

**All HGVS expressions:** `LRG_41:g.31350C>A`, `LRG_41t1:c.384C>A`, `NC_000011.10:g.33710129G>T`, `NC_000011.9:g.33731675G>T`, `NG_008057.1:g.31350C>A`, `NM_000611.6:c.384C>A`, `NM_001127223.1:c.384C>A`, `NM_001127225.2:c.384C>A`, `NM_001127226.2:c.384C>A`, `NM_001127227.2:c.384C>A`, `NM_203329.3:c.384C>A`, `NM_203330.2:c.384C>A`, `NM_203331.3:c.384C>A`

## 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 0.915, GERP -0.467, phastCons 0.5 — weakly conserved position
- CADD: **PHRED 6.911**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.99 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 **0.0178%** (eas) · FAF95 0.00884% · FAF99 0.00641% · 8/44,832 in the highest group · 9/1,611,266 alleles overall — ultra-rare (popmax 0.0178%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0178% | 5,604 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,398 |

*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}


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.


### 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-04.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-04 |

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

## Similar variants {#similar}

Related CD59 variant pages (same residue, condition, or type): [CD59 p.Pro128Ser](/variant/cd59-p-pro128ser), [CD59 p.Cys89Tyr](/variant/cd59-p-cys89tyr), [CD59 p.Met1Thr](/variant/cd59-p-met1thr), [CD59 p.Ala50Val](/variant/cd59-p-ala50val), [CD59 p.Arg78Cys](/variant/cd59-p-arg78cys), [CD59 p.Asn33Thr](/variant/cd59-p-asn33thr), [CD59 p.Asp92Asn](/variant/cd59-p-asp92asn), [CD59 p.Thr105Pro](/variant/cd59-p-thr105pro).

### 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 1943798). 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.*