# NM_000066.4(C8B):c.249G>T (p.Arg83Ser)

https://sugi.bio/variant/c8b-p-arg83ser

## Summary

**C8B p.Arg83Ser (c.249G>T)** is classified **Uncertain significance** in C8B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-02). AlphaMissense: ambiguous (0.5577); Ultra-rare (popmax 0.0178%, eas); Associated with type II complement component 8 deficiency.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs567145070 · 3 submitters · 1 linked condition · AlphaMissense ambiguous · ultra-rare (popmax 0.0178%, eas)

## For patients & families {#patients}

This is a change in the C8B gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 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.Arg83Ser |
| Coding change (HGVS c.) | c.249G>T |
| MANE Select transcript | [NM_000066](https://www.ncbi.nlm.nih.gov/nuccore/NM_000066) |
| dbSNP | [rs567145070](https://www.ncbi.nlm.nih.gov/snp/rs567145070/) |
| Variant type | single nucleotide variant |
| Location | chr1:56960020-56960020 (GRCh38) |
| ClinVar | [VCV2151875](https://www.ncbi.nlm.nih.gov/clinvar/variation/2151875/) |

**All HGVS expressions:** `LRG_31:g.10996G>T`, `LRG_31t1:c.249G>T`, `NC_000001.10:g.57425693C>A`, `NC_000001.11:g.56960020C>A`, `NG_007285.1:g.10996G>T`, `NM_000066.4:c.249G>T`, `NM_001278543.2:c.93G>T`, `NM_001278544.2:c.-67G>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; SaProt calls this damaging; REVEL does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5577) — no call either way
- REVEL 0.182 (moderately benign-leaning)
- SaProt LLR -11.126 (damaging)
- → **In-silico consensus:** SaProt calls this damaging; REVEL does not; AlphaMissense makes no call
- SpliceAI predicts **donor loss** (Δ 0.55) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.985, GERP 2.16, phastCons 1 — weakly conserved position
- CADD: **PHRED 27.2**. 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.*
- Regional missense constraint: **o/e 1.09** across the covering region of the MANE Select transcript (56,929,407–56,965,948), spanning 36,541 bp. Chi-square p 0.016. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.55**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.40** (loss), gain 0.02 / loss 0.40. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0178%** (eas) · FAF95 0.00884% · FAF99 0.00641% · 8/44,868 in the highest group · 16/1,614,082 alleles overall — ultra-rare (popmax 0.0178%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0178% | 5,608 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,833 |
| South Asian | 0.0011% | 91,068 |
| European (non-Finnish) | 0.000339% | 295,003 |

*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 **83** lies in a disulfide bond; a β-strand; the tsp type-1 1 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-02.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 3 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-31 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| 3billion | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-02 |

## 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, Nonpapillary renal cell carcinoma, none provided, 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.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), [C8B p.Arg136His](/variant/c8b-p-arg136his), [C8B p.Arg323Trp](/variant/c8b-p-arg323trp).

### 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 2151875). 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.*