# NM_000562.3(C8A):c.579del (p.Cys194fs)

https://sugi.bio/variant/c8a-p-cys194fs

## Summary

**C8A p.Cys194fs (c.579del)** is classified **Pathogenic** in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-15). Very rare (popmax 0.00161%, nfe).

**At a glance:** Pathogenic · review: Single submitter · rsID rs1228972002 · 1 submitter · very rare (popmax 0.00161%, nfe)

## For patients & families {#patients}

This is a change in the C8A gene that is reported as disease-causing, but on limited review, 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 | [C8A](https://sugi.bio/atlas/gene/C8A/) |
| Protein change (HGVS p.) | p.Cys194fs |
| Coding change (HGVS c.) | c.579del |
| MANE Select transcript | [NM_000562](https://www.ncbi.nlm.nih.gov/nuccore/NM_000562) |
| dbSNP | [rs1228972002](https://www.ncbi.nlm.nih.gov/snp/rs1228972002/) |
| Variant type | Deletion |
| Location | chr1:56881558-56881558 (GRCh38) |
| ClinVar | [VCV2968639](https://www.ncbi.nlm.nih.gov/clinvar/variation/2968639/) |

**All HGVS expressions:** `LRG_139:g.31790del`, `LRG_139t1:c.579del`, `NC_000001.10:g.57347232del`, `NC_000001.11:g.56881559del`, `NG_012049.1:g.31790del`, `NM_000562.3:c.579del`

## 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 -3.811, GERP -4.03 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.168, pLI 1.4084e-23. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 11**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 18.41**. 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: **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 (gnomAD v4.1): grpmax **0.00161%** (nfe) · FAF95 0.00103% · FAF99 0.00083% · 19/1,179,802 in the highest group · 19/1,613,706 alleles overall — very rare (popmax 0.00161%, 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}

**C8A** population constraint: LOEUF 1.168, pLI 1.4084e-23, missense-Z -0.23762. *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 **194** lies in a disulfide bond; a turn; the macpf domain.

AlphaFold model confidence (whole protein): pLDDT 79.58, 32% of residues very-high.

**11 experimental structure(s)** (PDB): [2QOS](https://www.rcsb.org/structure/2QOS), [2QQH](https://www.rcsb.org/structure/2QQH), [2RD7](https://www.rcsb.org/structure/2RD7), [3OJY](https://www.rcsb.org/structure/3OJY), [6H03](https://www.rcsb.org/structure/6H03), [6H04](https://www.rcsb.org/structure/6H04).

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

*Describes the biological roles of C8A (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.*


### Pathways affected {#pathways}

C8A participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Terminal pathway of complement](https://reactome.org/content/detail/R-HSA-166665) | curated |

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

**Biological process:** complement activation, killing of cells of another organism, complement activation, GZMK pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-15 |

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

## Similar variants {#similar}

Related C8A variant pages (same residue, condition, or type): [C8A c.655-4del](/variant/c8a-c-655-minus-4del), [C8A p.Ala153fs](/variant/c8a-p-ala153fs), [C8A p.Ala360fs](/variant/c8a-p-ala360fs), [C8A p.Thr72fs](/variant/c8a-p-thr72fs), [C8A p.Ser445del](/variant/c8a-p-ser445del), [C8A p.Val240_Lys241del](/variant/c8a-p-val240-lys241del).

### 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 2968639). 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.*