# NM_000733.4(CD3E):c.577A>G (p.Lys193Glu)

https://sugi.bio/variant/cd3e-p-lys193glu

## Summary

**CD3E p.Lys193Glu (c.577A>G)** is classified **Uncertain significance** in CD3E (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-23). AlphaMissense: likely pathogenic (0.7084); Very rare (popmax 0.000763%, nfe); Associated with CD3E-related disorder.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000763%, 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, and is linked to CD3E-related disorder.

*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.Lys193Glu |
| Coding change (HGVS c.) | c.577A>G |
| MANE Select transcript | [NM_000733](https://www.ncbi.nlm.nih.gov/nuccore/NM_000733) |
| Variant type | single nucleotide variant |
| Location | chr11:118315495-118315495 (GRCh38) |
| ClinVar | [VCV3355378](https://www.ncbi.nlm.nih.gov/clinvar/variation/3355378/) |

**All HGVS expressions:** `LRG_38:g.15916A>G`, `LRG_38t1:c.577A>G`, `NC_000011.10:g.118315495A>G`, `NC_000011.9:g.118186210A>G`, `NG_007383.1:g.15916A>G`, `NM_000733.4:c.577A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7084)
- REVEL 0.226 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -7.191 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 11.094, GERP 1.42, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.2**. 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 0.88** across the covering region of the MANE Select transcript (118,304,953–118,315,539), spanning 10,586 bp. Chi-square p 0.052. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.000763%** (nfe) · FAF95 0.000359% · FAF99 0.00026% · 9/1,179,760 in the highest group · 9/1,461,410 alleles overall — very rare (popmax 0.000763%, 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 **193** lies in an α-helix; the itam domain; the 'disordered' 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.Lys193Glu 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 No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-09-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-09-23 |

## Associated conditions {#conditions}

[CD3E-related disorder](https://sugi.bio/atlas/disease/cd3e-related-disorder/).

**Reported phenotype names (ClinVar):** CD3E-related disorder, CD3E-related condition.

## Similar variants {#similar}

Related CD3E variant pages (same residue, condition, or type): [CD3E p.Lys193=](/variant/cd3e-p-lys193), [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).

### 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 3355378). 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.*