# NM_000073.3(CD3G):c.496C>T (p.Arg166Ter)

https://sugi.bio/variant/cd3g-p-arg166ter

## Summary

**CD3G p.Arg166Ter (c.496C>T)** is classified **Pathogenic** in CD3G (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-24). Very rare (popmax 0.00446%, eas); Associated with combined immunodeficiency due to CD3gamma deficiency.

**At a glance:** Pathogenic · review: Single submitter · rsID rs201529449 · 1 submitter · 1 linked condition · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the CD3G gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to combined immunodeficiency due to CD3gamma 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 |
| Age of onset (of this condition) | Infancy |
| Diagnostic panels | CD3G is a diagnostic-grade gene on 3 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017046/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD3G](https://sugi.bio/atlas/gene/CD3G/) |
| Protein change (HGVS p.) | p.Arg166Ter |
| Coding change (HGVS c.) | c.496C>T |
| MANE Select transcript | [NM_000073](https://www.ncbi.nlm.nih.gov/nuccore/NM_000073) |
| dbSNP | [rs201529449](https://www.ncbi.nlm.nih.gov/snp/rs201529449/) |
| Variant type | single nucleotide variant |
| Location | chr11:118352416-118352416 (GRCh38) |
| ClinVar | [VCV1457956](https://www.ncbi.nlm.nih.gov/clinvar/variation/1457956/) |

**All HGVS expressions:** `LRG_39:g.13073C>T`, `NC_000011.10:g.118352416C>T`, `NC_000011.9:g.118223131C>T`, `NG_007566.1:g.13073C>T`, `NM_000073.3:c.496C>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 2.215, GERP 1.07, phastCons 0.978 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.191, pLI 8.383e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 7**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 37.0**. 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 **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000276% · 2/44,884 in the highest group · 9/1,613,858 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,442 |
| African / African-American | 0.00267% | 37,495 |
| European (non-Finnish) | 0.000424% | 235,964 |

*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}

**CD3G** population constraint: LOEUF 1.191, pLI 8.383e-07, missense-Z 0.13555; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **combined immunodeficiency due to CD3gamma deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **166** lies in an α-helix; the itam domain.

AlphaFold model confidence (whole protein): pLDDT 75.05, 23% of residues very-high.

**38 experimental structure(s)** (PDB): [6JXR](https://www.rcsb.org/structure/6JXR), [7FJD](https://www.rcsb.org/structure/7FJD), [7FJE](https://www.rcsb.org/structure/7FJE), [7FJF](https://www.rcsb.org/structure/7FJF), [7PHR](https://www.rcsb.org/structure/7PHR), [7Q5U](https://www.rcsb.org/structure/7Q5U).

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

*Describes the biological roles of CD3G (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:** CD3G's established molecular role includes transmembrane signaling receptor activity. p.Arg166Ter falls in the itam domain. In Reactome, CD3G is annotated in disease pathway(s) including **FCGR3A-mediated IL10 synthesis**, **FCGR3A-mediated phagocytosis**.

**Disease mechanism (Reactome):** CD3G loss or alteration is curated in [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323), [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422).

### Pathways affected {#pathways}

CD3G participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | curated |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | curated |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [Co-inhibition by PD-1](https://reactome.org/content/detail/R-HSA-389948) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [Generation of second messenger molecules](https://reactome.org/content/detail/R-HSA-202433) | curated |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |
| [Phosphorylation of CD3 and TCR zeta chains](https://reactome.org/content/detail/R-HSA-202427) | curated |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | curated |
| [Role of phospholipids in phagocytosis](https://reactome.org/content/detail/R-HSA-2029485) | curated |
| [Translocation of ZAP-70 to Immunological synapse](https://reactome.org/content/detail/R-HSA-202430) | curated |
| [FCGR activation](https://reactome.org/content/detail/R-HSA-2029481) | electronic |

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

**Molecular function:** transmembrane signaling receptor activity, identical protein binding.

**Biological process:** establishment or maintenance of cell polarity, cell surface receptor signaling pathway, protein transport, T cell receptor signaling pathway, regulation of lymphocyte apoptotic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-24.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-24 |

## Associated conditions {#conditions}

[combined immunodeficiency due to CD3gamma deficiency](https://sugi.bio/atlas/disease/combined-immunodeficiency-due-to-cd3gamma-deficiency/).

**Reported phenotype names (ClinVar):** Combined immunodeficiency due to CD3gamma deficiency, Immunodeficiency 17, CD3-GAMMA DEFICIENCY, SCID-LIKE IMMUNODEFICIENCY, T CELL-PARTIAL, B CELL-POSITIVE, NK CELL-POSITIVE, Immunodeficiency 17, CD3 gamma deficient.

## Similar variants {#similar}

Related CD3G variant pages (same residue, condition, or type): [CD3G p.Arg166Gln](/variant/cd3g-p-arg166gln), [CD3G p.Arg166=](/variant/cd3g-p-arg166), [CD3G c.55+1G>T](/variant/cd3g-c-55-plus-1g-t), [CD3G c.56-1G>A](/variant/cd3g-c-56-minus-1g-a), [CD3G p.Lys69Ter](/variant/cd3g-p-lys69ter), [CD3G p.Met1Val](/variant/cd3g-p-met1val), [CD3G c.*308G>A](/variant/cd3g-c-star-308g-a), [CD3G p.Arg146Thr](/variant/cd3g-p-arg146thr).

### 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 1457956). 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.*