# NM_000733.4(CD3E):c.173del (p.Leu58fs)

https://sugi.bio/variant/cd3e-p-leu58fs

## Summary

**CD3E p.Leu58fs (c.173del)** is classified **Pathogenic** in CD3E (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-01).

**At a glance:** Pathogenic · review: Multiple submitters · 2 submitters

## For patients & families {#patients}

This is a change in the CD3E gene that is considered disease-causing, submitted by 2 submitters.

*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 | [CD3E](https://sugi.bio/atlas/gene/CD3E/) |
| Protein change (HGVS p.) | p.Leu58fs |
| Coding change (HGVS c.) | c.173del |
| MANE Select transcript | [NM_000733](https://www.ncbi.nlm.nih.gov/nuccore/NM_000733) |
| Variant type | Deletion |
| Location | chr11:118312687-118312687 (GRCh38) |
| ClinVar | [VCV3340358](https://www.ncbi.nlm.nih.gov/clinvar/variation/3340358/) |

**All HGVS expressions:** `LRG_38:g.13108del`, `LRG_38t1:c.173del`, `NC_000011.10:g.118312687del`, `NC_000011.9:g.118183402del`, `NG_007383.1:g.13108del`, `NM_000733.3:c.173delT`, `NM_000733.4:c.173del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -5.443, GERP -2.82 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.659, pLI 0.46931. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 9**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**CD3E** population constraint: LOEUF 0.659, pLI 0.46931, missense-Z 0.88647; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (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):

- **immunodeficiency 18** — Definitive (AR)

## Protein context {#protein}

Residue **58** lies in a disulfide bond; a β-strand; the ig-like domain.

AlphaFold model confidence (whole protein): pLDDT 73.56, 30% of residues very-high.

**44 experimental structure(s)** (PDB): [1A81](https://www.rcsb.org/structure/1A81), [1SY6](https://www.rcsb.org/structure/1SY6), [1XIW](https://www.rcsb.org/structure/1XIW), [2ROL](https://www.rcsb.org/structure/2ROL), [5QU2](https://www.rcsb.org/structure/5QU2), [6JXR](https://www.rcsb.org/structure/6JXR).

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

*Describes the biological roles of CD3E (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:** CD3E's established molecular role includes transmembrane signaling receptor activity. p.Leu58fs falls in the ig-like domain.


### Pathways affected {#pathways}

CD3E participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |
| [Translocation of ZAP-70 to Immunological synapse](https://reactome.org/content/detail/R-HSA-202430) | curated |

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

**Molecular function:** transmembrane signaling receptor activity, SH3 domain binding, protein-macromolecule adaptor activity, identical protein binding.

**Biological process:** positive regulation of gene expression, negative regulation of gene expression, positive regulation of T cell proliferation, T cell receptor signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-01.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-25 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-01 |

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

## Similar variants {#similar}

Related CD3E variant pages (same residue, condition, or type): [CD3E p.Gly143fs](/variant/cd3e-p-gly143fs), [CD3E p.Ser88fs](/variant/cd3e-p-ser88fs), [CD3E c.567+65_567+66del](/variant/cd3e-c-567-plus-65-567-plus-66del), [CD3E c.70+4del](/variant/cd3e-c-70-plus-4del), [CD3E p.Gly68_Gly76del](/variant/cd3e-p-gly68-gly76del), [CD3E p.Lys177fs](/variant/cd3e-p-lys177fs), [CD3E c.353-5del](/variant/cd3e-c-353-minus-5del), [CD3E c.50-10del](/variant/cd3e-c-50-minus-10del).

### 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 3340358). 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.*