# NM_001002029.3:c.(?_3231)_(3387_?)del

https://sugi.bio/variant/c4b-c-3231

## Summary

**C4B c.(?_3231** is classified **Pathogenic** in C4B (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-04). Associated with complement component 4b deficiency.

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

## For patients & families {#patients}

This is a change in the C4B gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to complement component 4b 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 | C4B is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015797/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [C4B](https://sugi.bio/atlas/gene/C4B/) |
| Coding change (HGVS c.) | c.(?_3231 |
| MANE Select transcript | [NM_007293](https://www.ncbi.nlm.nih.gov/nuccore/NM_007293) (variant reported on NM_001002029) |
| Variant type | Deletion |
| ClinVar | [VCV987922](https://www.ncbi.nlm.nih.gov/clinvar/variation/987922/) |

**All HGVS expressions:** `LRG_138t1:c.(?_3231)_(3387_?)del`

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.56, 45% of residues very-high.

**12 experimental structure(s)** (PDB): [1HZF](https://www.rcsb.org/structure/1HZF), [5JPM](https://www.rcsb.org/structure/5JPM), [5JPN](https://www.rcsb.org/structure/5JPN), [5JTW](https://www.rcsb.org/structure/5JTW), [6YSQ](https://www.rcsb.org/structure/6YSQ), [7B2M](https://www.rcsb.org/structure/7B2M).

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

*Describes the biological roles of C4B (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.*

**How this variant is thought to act:** C4B's established molecular role includes complement component C1q complex binding. In Reactome, C4B is annotated in disease pathway(s) including **Dengue virus activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** C4B loss or alteration is curated in [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588).

### Pathways affected {#pathways}

C4B participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588) | curated |
| [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 |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |

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

**Molecular function:** complement component C1q complex binding.

**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 2020-10-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dubai Health Genomic Medicine Center, Dubai Health | Pathogenic | criteria provided, single submitter | clinical testing | 2020-10-04 |

## Associated conditions {#conditions}

[complement component 4b deficiency](https://sugi.bio/atlas/disease/complement-component-4b-deficiency/).

**Reported phenotype names (ClinVar):** Complement component 4b deficiency.

## Similar variants {#similar}

Related C4B variant pages (same residue, condition, or type): [C4B c.3230+1G>A](/variant/c4b-c-3230-plus-1g-a), [C4B c.3676+1G>A](/variant/c4b-c-3676-plus-1g-a), [C4B c.3504+32G>A](/variant/c4b-c-3504-plus-32g-a), [C4B p.Ala1148Thr](/variant/c4b-p-ala1148thr), [C4B p.Arg1072Trp](/variant/c4b-p-arg1072trp).

### 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 2026-07-14); 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 987922). 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.*