# NM_000063.6(C2):c.237_240del (p.Ser80fs)

https://sugi.bio/variant/c2-p-ser80fs

## Summary

**C2 p.Ser80fs (c.237_240del)** is classified **Pathogenic** in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). Very rare (popmax 0.000678%, nfe); Associated with Primary immunodeficiency or monogenic inflammatory bowel disease.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.000678%, nfe)

## For patients & families {#patients}

This is a change in the C2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Primary immunodeficiency or monogenic inflammatory bowel disease.

*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 | [C2](https://sugi.bio/atlas/gene/C2/) |
| Protein change (HGVS p.) | p.Ser80fs |
| Coding change (HGVS c.) | c.237_240del |
| MANE Select transcript | [NM_000063](https://www.ncbi.nlm.nih.gov/nuccore/NM_000063) |
| Variant type | Deletion |
| Location | chr6:31928142-31928145 (GRCh38) |
| ClinVar | [VCV4887050](https://www.ncbi.nlm.nih.gov/clinvar/variation/4887050/) |

**All HGVS expressions:** `LRG_26:g.5657_5660del`, `LRG_26t1:c.237_240del`, `NC_000006.11:g.31895922_31895925del`, `NC_000006.12:g.31928145_31928148del`, `NG_011730.1:g.5657_5660del`, `NM_000063.6:c.237_240del`, `NM_001145903.3:c.46+347_46+350del`, `NM_001178063.3:c.74-5465_74-5462del`, `NM_001282457.2:c.-63-5465_-63-5462del`, `NM_001282458.2:c.122_125del`, `NM_001282459.2:c.237_240del`

## 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 0.487, GERP -1.24, phastCons 0.002 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.909, pLI 2.4382e-16. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 18**, 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.
- Population frequency (gnomAD v4.1): grpmax **0.000678%** (nfe) · FAF95 0.000292% · FAF99 0.000211% · 8/1,179,818 in the highest group · 8/1,611,754 alleles overall — very rare (popmax 0.000678%, 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}

**C2** population constraint: LOEUF 0.909, pLI 2.4382e-16, missense-Z 2.3109. *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 **80** lies in the sushi 1 domain.

AlphaFold model confidence (whole protein): pLDDT 88.61, 66% of residues very-high.

**14 experimental structure(s)** (PDB): [2I6Q](https://www.rcsb.org/structure/2I6Q), [2I6S](https://www.rcsb.org/structure/2I6S), [3ERB](https://www.rcsb.org/structure/3ERB), [8ACF](https://www.rcsb.org/structure/8ACF), [8ACI](https://www.rcsb.org/structure/8ACI), [9QJ4](https://www.rcsb.org/structure/9QJ4).

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

*Describes the biological roles of C2 (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}

C2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of C3 and C5](https://reactome.org/content/detail/R-HSA-174577) | curated |
| [Initial triggering of complement](https://reactome.org/content/detail/R-HSA-166663) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Biological process:** complement activation, complement activation, GZMK pathway, positive regulation of apoptotic cell clearance.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-28 |

## Associated conditions {#conditions}

[Primary immunodeficiency or monogenic inflammatory bowel disease](https://sugi.bio/atlas/disease/primary-immunodeficiency-or-monogenic-inflammatory-bowel-disease/).

**Reported phenotype names (ClinVar):** Primary immunodeficiency or monogenic inflammatory bowel disease.

## Similar variants {#similar}

Related C2 variant pages (same residue, condition, or type): [ZBTB12 p.Ile80=](/variant/zbtb12-p-ile80), [C2 c.841_849+19del](/variant/c2-c-841-849-plus-19del), [C2 p.Ala495fs](/variant/c2-p-ala495fs), [C2 p.Pro207fs](/variant/c2-p-pro207fs), [C2 p.Ser186Cys](/variant/c2-p-ser186cys), [C2 c.1455+17del](/variant/c2-c-1455-plus-17del), [C2 c.1567+22_1567+43del](/variant/c2-c-1567-plus-22-1567-plus-43del), [C2 c.1811-16del](/variant/c2-c-1811-minus-16del).

### 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 4887050). 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.*