# NM_000066.4(C8B):c.138del (p.Phe47fs)

https://sugi.bio/variant/c8b-p-phe47fs

## Summary

**C8B p.Phe47fs (c.138del)** is classified **Pathogenic/Likely pathogenic** in C8B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-17). Very rare (popmax 0.00167%, amr); Associated with type II complement component 8 deficiency.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs779205550 · 2 submitters · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the C8B gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to type II complement component 8 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 | C8B is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010625/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [C8B](https://sugi.bio/atlas/gene/C8B/) |
| Protein change (HGVS p.) | p.Phe47fs |
| Coding change (HGVS c.) | c.138del |
| MANE Select transcript | [NM_000066](https://www.ncbi.nlm.nih.gov/nuccore/NM_000066) |
| dbSNP | [rs779205550](https://www.ncbi.nlm.nih.gov/snp/rs779205550/) |
| Variant type | Deletion |
| Location | chr1:56960131-56960131 (GRCh38) |
| ClinVar | [VCV2174163](https://www.ncbi.nlm.nih.gov/clinvar/variation/2174163/) |

**All HGVS expressions:** `LRG_31:g.10885del`, `LRG_31t1:c.138del`, `NC_000001.10:g.57425804del`, `NC_000001.11:g.56960131del`, `NG_007285.1:g.10885del`, `NM_000066.4:c.138del`, `NM_001278543.2:c.-19del`, `NM_001278544.2:c.-178del`

## 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 1.422, GERP -2.21, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.18, pLI 1.1001e-21. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 12**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 27.5**. 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 **0.00167%** (amr) · FAF95 7.9e-05% · FAF99 5.4e-05% · 1/60,004 in the highest group · 5/1,614,054 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 60,004 |
| European (non-Finnish) | 0.000339% | 295,004 |

*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}

**C8B** population constraint: LOEUF 1.18, pLI 1.1001e-21, missense-Z -0.21839. *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 81.99, 49% of residues very-high.

**8 experimental structure(s)** (PDB): [3OJY](https://www.rcsb.org/structure/3OJY), [6H03](https://www.rcsb.org/structure/6H03), [6H04](https://www.rcsb.org/structure/6H04), [7NYC](https://www.rcsb.org/structure/7NYC), [7NYD](https://www.rcsb.org/structure/7NYD), [8B0F](https://www.rcsb.org/structure/8B0F).

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

*Describes the biological roles of C8B (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}

C8B 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-17.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-10-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-17 |

## Associated conditions {#conditions}

[type II complement component 8 deficiency](https://sugi.bio/atlas/disease/type-ii-complement-component-8-deficiency/).

**Reported phenotype names (ClinVar):** Type II complement component 8 deficiency, not provided, none provided, COMPLEMENT C8 DEFICIENCY, TYPE II, C8 BETA DEFICIENCY, C8B DEFICIENCY, COMPLEMENT COMPONENT 8B DEFICIENCY.

## Similar variants {#similar}

Related C8B variant pages (same residue, condition, or type): [C8B p.Asn113fs](/variant/c8b-p-asn113fs), [C8B p.Pro202fs](/variant/c8b-p-pro202fs), [C8B p.Arg284Ter](/variant/c8b-p-arg284ter), [C8B p.Arg428Ter](/variant/c8b-p-arg428ter), [C8B p.Gln91Ter](/variant/c8b-p-gln91ter), [C8B p.Trp9Ter](/variant/c8b-p-trp9ter), [C8B p.Ala461Ser](/variant/c8b-p-ala461ser), [C8B p.Ala480Thr](/variant/c8b-p-ala480thr).

### 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 2174163). 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.*