# NM_000066.4(C8B):c.102G>A (p.Arg34=)

https://sugi.bio/variant/c8b-p-arg34

## Summary

**C8B p.Arg34= (c.102G>A)** is classified **Likely benign** in C8B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-19). Very rare (popmax 0.00223%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs1645157358 · 1 submitter · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the C8B gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.Arg34= |
| Coding change (HGVS c.) | c.102G>A |
| MANE Select transcript | [NM_000066](https://www.ncbi.nlm.nih.gov/nuccore/NM_000066) |
| dbSNP | [rs1645157358](https://www.ncbi.nlm.nih.gov/snp/rs1645157358/) |
| Variant type | single nucleotide variant |
| Location | chr1:56960167-56960167 (GRCh38) |
| ClinVar | [VCV3005644](https://www.ncbi.nlm.nih.gov/clinvar/variation/3005644/) |

**All HGVS expressions:** `LRG_31:g.10849G>A`, `LRG_31t1:c.102G>A`, `NC_000001.10:g.57425840C>T`, `NC_000001.11:g.56960167C>T`, `NG_007285.1:g.10849G>A`, `NM_000066.4:c.102G>A`, `NM_001278543.2:c.-55G>A`, `NM_001278544.2:c.-214G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.696, GERP -1.71 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.485**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain, 9 bp away.
- 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000183% · FAF99 0.00012% · 1/44,870 in the highest group · 10/1,461,846 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,254 |
| East Asian (grpmax) | 0.00223% | 44,870 |
| African / African-American | 0.00133% | 75,026 |
| European (non-Finnish) | 0.000508% | 196,667 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-19.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-19 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## 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.Cys508Ter](/variant/c8b-p-cys508ter), [C8B p.Gln91Ter](/variant/c8b-p-gln91ter), [C8B p.Trp9Ter](/variant/c8b-p-trp9ter), [C8B p.Ala21Thr](/variant/c8b-p-ala21thr), [C8B p.Ala446Val](/variant/c8b-p-ala446val), [C8B p.Ala461Ser](/variant/c8b-p-ala461ser).

### 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 3005644). 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.*