# NM_001783.4(CD79A):c.498G>C (p.Arg166Ser)

https://sugi.bio/variant/cd79a-p-arg166ser

## Summary

**CD79A p.Arg166Ser (c.498G>C)** is classified **Uncertain significance** in CD79A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-03). AlphaMissense: likely pathogenic (0.962); Very rare (popmax 0.000171%, nfe); Associated with agammaglobulinemia 3, autosomal recessive.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2123305225 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000171%, nfe)

## For patients & families {#patients}

This is a change in the CD79A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to agammaglobulinemia 3, autosomal recessive.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015673/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD79A](https://sugi.bio/atlas/gene/CD79A/) |
| Protein change (HGVS p.) | p.Arg166Ser |
| Coding change (HGVS c.) | c.498G>C |
| MANE Select transcript | [NM_001783](https://www.ncbi.nlm.nih.gov/nuccore/NM_001783) |
| dbSNP | [rs2123305225](https://www.ncbi.nlm.nih.gov/snp/rs2123305225/) |
| Variant type | single nucleotide variant |
| Location | chr19:41879653-41879653 (GRCh38) |
| ClinVar | [VCV1474994](https://www.ncbi.nlm.nih.gov/clinvar/variation/1474994/) |

**All HGVS expressions:** `LRG_42:g.7534G>C`, `NC_000019.10:g.41879653G>C`, `NC_000019.9:g.42383723G>C`, `NG_009619.1:g.7534G>C`, `NM_001783.4:c.498G>C`, `NM_021601.4:c.384G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.962)
- REVEL 0.569 (indeterminate)
- SaProt LLR -8.244 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.62) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.577, GERP 1.48, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.79** across the covering region of the MANE Select transcript (41,877,305–41,880,977), spanning 3,672 bp. Chi-square p 0.00029. 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 **0.62**, acceptor gain **0.01**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.62**, acceptor gain **0.01**, donor gain **0.00**.
- Pangolin: Δ**0.66** (loss), gain 0.03 / loss 0.66. 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 **0.000171%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,169,094 in the highest group · 2/1,600,622 alleles overall — very rare (popmax 0.000171%, nfe).

*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}

**CD79A** population constraint: LOEUF 0.991, pLI 0.0010109, missense-Z 1.1783. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **agammaglobulinemia 3, autosomal recessive** — Definitive (AR)

## Protein context {#protein}

Residue **166** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 77.56, 39% of residues very-high.

**6 experimental structure(s)** (PDB): [1CV9](https://www.rcsb.org/structure/1CV9), [7WSO](https://www.rcsb.org/structure/7WSO), [7WSP](https://www.rcsb.org/structure/7WSP), [7XQ8](https://www.rcsb.org/structure/7XQ8), [7XT6](https://www.rcsb.org/structure/7XT6), [9E6G](https://www.rcsb.org/structure/9E6G).

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

*Describes the biological roles of CD79A (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:** CD79A's established molecular role includes identical protein binding. In Reactome, CD79A is annotated in disease pathway(s) including **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** CD79A loss or alteration is curated in [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

CD79A participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [CD22 mediated BCR regulation](https://reactome.org/content/detail/R-HSA-5690714) | curated |
| [Affinity selection of immunoglobulins](https://reactome.org/content/detail/R-HSA-9938027) | electronic |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |

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

**Molecular function:** identical protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-03-03.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-03-03 |

## Associated conditions {#conditions}

[agammaglobulinemia 3, autosomal recessive](https://sugi.bio/atlas/disease/agammaglobulinemia-3-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Agammaglobulinemia 3, autosomal recessive, AGAMMAGLOBULINEMIA 3, AGAMMAGLOBULINEMIA, AUTOSOMAL RECESSIVE, DUE TO CD79A DEFECT.

## Similar variants {#similar}

Related CD79A variant pages (same residue, condition, or type): [CD79A p.Arg124Cys](/variant/cd79a-p-arg124cys), [CD79A p.Arg124His](/variant/cd79a-p-arg124his), [CD79A p.Arg168Gln](/variant/cd79a-p-arg168gln), [CD79A p.Arg204Gln](/variant/cd79a-p-arg204gln), [CD79A p.Asn60Ser](/variant/cd79a-p-asn60ser), [CD79A p.Asn63Ser](/variant/cd79a-p-asn63ser), [CD79A p.Gly179Arg](/variant/cd79a-p-gly179arg), [CD79A p.Ile151Thr](/variant/cd79a-p-ile151thr).

### 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 1474994). 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.*