# NM_000733.4(CD3E):c.567G>A (p.Glu189=)

https://sugi.bio/variant/cd3e-p-glu189

## Summary

**CD3E p.Glu189= (c.567G>A)** is classified **Uncertain significance** in CD3E (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-06). Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the CD3E gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [CD3E](https://sugi.bio/atlas/gene/CD3E/) |
| Protein change (HGVS p.) | p.Glu189= |
| Coding change (HGVS c.) | c.567G>A |
| MANE Select transcript | [NM_000733](https://www.ncbi.nlm.nih.gov/nuccore/NM_000733) |
| Variant type | single nucleotide variant |
| Location | chr11:118314494-118314494 (GRCh38) |
| ClinVar | [VCV4689608](https://www.ncbi.nlm.nih.gov/clinvar/variation/4689608/) |

**All HGVS expressions:** `LRG_38:g.14915G>A`, `LRG_38t1:c.567G>A`, `NC_000011.10:g.118314494G>A`, `NC_000011.9:g.118185209G>A`, `NG_007383.1:g.14915G>A`, `NM_000733.4:c.567G>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 **donor loss** (Δ 0.69) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.694, GERP 1.73, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.3**. 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 **0.32**, donor loss **0.69**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.69**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.73** (loss), gain 0.01 / loss 0.73. 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 **8.48e-05%** (nfe) · 1/1,179,804 in the highest group · 1/1,461,574 alleles overall — very rare (popmax 8.48e-05%, 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}

**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 **189** lies in the itam domain; the 'disordered' region; the 'numb-binding region' region.

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.Glu189= falls in the itam 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-06.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-06 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CD3E variant pages (same residue, condition, or type): [CD3E c.103+1G>A](/variant/cd3e-c-103-plus-1g-a), [CD3E c.49+1G>C](/variant/cd3e-c-49-plus-1g-c), [CD3E p.Tyr96Ter](/variant/cd3e-p-tyr96ter), [CD3E c.520+5G>A](/variant/cd3e-c-520-plus-5g-a), [CD3E p.Arg192Gln](/variant/cd3e-p-arg192gln), [CD3E p.Arg206His](/variant/cd3e-p-arg206his), [CD3E p.Asn25Asp](/variant/cd3e-p-asn25asp), [CD3E p.Asn74Thr](/variant/cd3e-p-asn74thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 4689608). 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.*