# NM_001735.3(C5):c.3463del (p.Ala1155fs)

https://sugi.bio/variant/c5-p-ala1155fs

## Summary

**C5 p.Ala1155fs (c.3463del)** is classified **Likely pathogenic** in C5 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-07). Associated with complement component 5 deficiency.

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

## For patients & families {#patients}

This is a change in the C5 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to complement component 5 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 |
| Diagnostic panels | C5 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002191/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [C5](https://sugi.bio/atlas/gene/C5/) |
| Protein change (HGVS p.) | p.Ala1155fs |
| Coding change (HGVS c.) | c.3463del |
| MANE Select transcript | [NM_001735](https://www.ncbi.nlm.nih.gov/nuccore/NM_001735) |
| Variant type | Deletion |
| Location | chr9:120981867-120981867 (GRCh38) |
| ClinVar | [VCV4876711](https://www.ncbi.nlm.nih.gov/clinvar/variation/4876711/) |

**All HGVS expressions:** `LRG_28:g.73410del`, `LRG_28t1:c.3462del`, `NC_000009.11:g.123744146del`, `NC_000009.12:g.120981868del`, `NG_007364.1:g.73410del`, `NM_001317163.2:c.3481del`, `NM_001735.3:c.3463del`

## 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 8.394, GERP 1.36, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.779, pLI 7.7641e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 27 of 41**, so the transcript is predicted to undergo NMD.
- 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.

*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}

**C5** population constraint: LOEUF 0.779, pLI 7.7641e-17, missense-Z 2.3738. *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 **1155** lies in an α-helix; a disulfide bond; a UniProt-annotated variant site (in c5d).

AlphaFold model confidence (whole protein): pLDDT 81.67, 25% of residues very-high.

**49 experimental structure(s)** (PDB): [1CFA](https://www.rcsb.org/structure/1CFA), [1KJS](https://www.rcsb.org/structure/1KJS), [1XWE](https://www.rcsb.org/structure/1XWE), [22CR](https://www.rcsb.org/structure/22CR), [22GK](https://www.rcsb.org/structure/22GK), [22GL](https://www.rcsb.org/structure/22GL).

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

*Describes the biological roles of C5 (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}

C5 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of C3 and C5](https://reactome.org/content/detail/R-HSA-174577) | curated |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |
| [Peptide ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375276) | curated |
| [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:** positive regulation of vascular endothelial growth factor production, negative regulation of macrophage chemotaxis, positive regulation of chemokine production, complement activation, GZMK pathway.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-07-07.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Medgenome Labs Ltd | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-07-07 |

## Associated conditions {#conditions}

[complement component 5 deficiency](https://sugi.bio/atlas/disease/complement-component-5-deficiency/).

**Reported phenotype names (ClinVar):** Complement component 5 deficiency, C5 DEFICIENCY.

## Similar variants {#similar}

Related C5 variant pages (same residue, condition, or type): [C5 p.Val1446fs](/variant/c5-p-val1446fs), [C5 p.Ala1155Thr](/variant/c5-p-ala1155thr), [C5 c.2257+1G>A](/variant/c5-c-2257-plus-1g-a), [C5 c.4679-2A>G](/variant/c5-c-4679-minus-2a-g), [C5 p.Arg1476Ter](/variant/c5-p-arg1476ter), [C5 p.Gln19Ter](/variant/c5-p-gln19ter), [C5 p.Trp469Ter](/variant/c5-p-trp469ter), [C5 c.2059+3A>G](/variant/c5-c-2059-plus-3a-g).

### 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 4876711). 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.*