# NM_000066.4(C8B):c.1282C>T (p.Arg428Ter)

https://sugi.bio/variant/c8b-p-arg428ter

## Summary

**C8B p.Arg428Ter (c.1282C>T)** is classified **Pathogenic** in C8B (ClinVar, Multiple submitters, 19 submitters; last evaluated 2026-04-21). Rare (popmax 0.297%, mid); Associated with C8B-related disorders.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs41286844 · 19 submitters · 3 linked conditions · rare (popmax 0.297%, mid)

## For patients & families {#patients}

This is a change in the C8B gene that is considered disease-causing, submitted by 19 submitters, and is linked to C8B-related disorders.

*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 | [C8B](https://sugi.bio/atlas/gene/C8B/) |
| Protein change (HGVS p.) | p.Arg428Ter |
| Coding change (HGVS c.) | c.1282C>T |
| MANE Select transcript | [NM_000066](https://www.ncbi.nlm.nih.gov/nuccore/NM_000066) |
| dbSNP | [rs41286844](https://www.ncbi.nlm.nih.gov/snp/rs41286844/) |
| Variant type | single nucleotide variant |
| Location | chr1:56940965-56940965 (GRCh38) |
| ClinVar | [VCV17038](https://www.ncbi.nlm.nih.gov/clinvar/variation/17038/) |

**All HGVS expressions:** `LRG_31:g.30051C>T`, `LRG_31t1:c.1282C>T`, `NC_000001.10:g.57406638G>A`, `NC_000001.11:g.56940965G>A`, `NG_007285.1:g.30051C>T`, `NM_000066.4:c.1282C>T`, `NM_001278543.2:c.1126C>T`, `NM_001278544.2:c.1096C>T`

## 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 4.102, GERP 0.149, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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 9 of 12**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 40.0**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.297%** (mid) · FAF95 0.192% · FAF99 0.159% · 18/6,062 in the highest group · 2,134/1,613,758 alleles overall — rare (popmax 0.297%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.297% | 337 |
| European (non-Finnish) | 0.159% | 630 |
| Remaining individuals (not grpmax-eligible) | 0.128% | 781 |
| Admixed American | 0.0767% | 1,304 |
| Finnish (not grpmax-eligible) | 0.0687% | 1,455 |
| South Asian | 0.0406% | 2,461 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0372% | 2,691 |
| African / African-American | 0.0321% | 3,120 |
| East Asian | 0.00446% | 22,409 |

*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}

Residue **428** lies in a UniProt-annotated variant site (in c8d2); the macpf domain.

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** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-21.

**Submitter consensus:** unanimous (19/19 Pathogenic).

**Submission history:** 19 submissions (2009–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2014-04-24 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Pathogenic | no assertion criteria provided | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-29 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2024-04-29 |
| Clinical Genomics Laboratory, Washington University in St. Louis | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-25 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2018-08-08 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2009-09-01 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | criteria provided, single submitter | research | 2023-05-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-02-02 |
| Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Pathogenic | no assertion criteria provided | clinical testing | 2019-08-13 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2019-11-27 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Pathogenic | no assertion criteria provided | clinical testing |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-07-15 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Pathogenic | criteria provided, single submitter | research | 2023-08-25 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-13 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-21 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-20 |

## Associated conditions {#conditions}

[C8B-related disorders](https://sugi.bio/atlas/disease/c8b-related-disorders/), [complement component 6 deficiency](https://sugi.bio/atlas/disease/complement-component-6-deficiency/), [type II complement component 8 deficiency](https://sugi.bio/atlas/disease/type-ii-complement-component-8-deficiency/).

**Reported phenotype names (ClinVar):** C8B-related disorders, Type II complement component 8 deficiency, not provided, Complement component 6 deficiency, C8B-related disorder, C8B-related condition, C8 BETA DEFICIENCY, C8B DEFICIENCY, COMPLEMENT COMPONENT 8B DEFICIENCY, COMPLEMENT C8 DEFICIENCY, TYPE II.

## Similar variants {#similar}

Related C8B variant pages (same residue, condition, or type): [C8B p.Arg428Gln](/variant/c8b-p-arg428gln), [C8B p.Arg284Ter](/variant/c8b-p-arg284ter), [C8B p.Cys508Ter](/variant/c8b-p-cys508ter), [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), [C8B p.Arg136His](/variant/c8b-p-arg136his).

### 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 17038). 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.*