# NM_000733.4(CD3E):c.580G>A (p.Gly194Ser)

https://sugi.bio/variant/cd3e-p-gly194ser

## Summary

**CD3E p.Gly194Ser (c.580G>A)** is classified **Uncertain significance** in CD3E (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-06-20). AlphaMissense: ambiguous (0.504); Ultra-rare (popmax 0.0457%, nfe); Associated with immunodeficiency 18.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs141553540 · 5 submitters · 1 linked condition · AlphaMissense ambiguous · ultra-rare (popmax 0.0457%, 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 5 submitters, and is linked to immunodeficiency 18.

*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 | CD3E is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Recurrent infections — Very frequent (99-80%)
- Lymphopenia — Frequent (79-30%)
- Fever — Frequent (79-30%)
- Decreased circulating total IgA — Frequent (79-30%)
- Decreased circulating IgG level — Frequent (79-30%)
- Failure to thrive secondary to recurrent infections — Frequent (79-30%)
- Decreased lymphocyte proliferation in response to mitogen — Frequent (79-30%)
- Decreased proportion of CD3-positive T cells — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018295/index) · [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.Gly194Ser |
| Coding change (HGVS c.) | c.580G>A |
| MANE Select transcript | [NM_000733](https://www.ncbi.nlm.nih.gov/nuccore/NM_000733) |
| dbSNP | [rs141553540](https://www.ncbi.nlm.nih.gov/snp/rs141553540/) |
| Variant type | single nucleotide variant |
| Location | chr11:118315498-118315498 (GRCh38) |
| ClinVar | [VCV302664](https://www.ncbi.nlm.nih.gov/clinvar/variation/302664/) |

**All HGVS expressions:** `LRG_38:g.15919G>A`, `LRG_38t1:c.580G>A`, `NC_000011.10:g.118315498G>A`, `NC_000011.9:g.118186213G>A`, `NG_007383.1:g.15919G>A`, `NM_000733.4:c.580G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.504) — no call either way
- REVEL 0.278 (benign-leaning)
- SaProt LLR -6.132 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 11.719, GERP 1.42, phastCons 1 — highly conserved
- CADD: **PHRED 28.6**. 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 **0.0457%** (nfe) · FAF95 0.0425% · FAF99 0.0412% · 539/1,179,850 in the highest group · 552/1,613,276 alleles overall — ultra-rare (popmax 0.0457%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0457% | 2,189 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,414 |
| African / African-American | 0.00936% | 10,679 |

*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 **194** 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.Gly194Ser 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-06-20.

**Submitter consensus:** conflicting (4 Uncertain significance, 1 Uncertain Significance).

**Submission history:** 5 submissions (2018–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-20 |
| Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-03-30 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain Significance | criteria provided, single submitter | clinical testing |  |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-14 |

## Associated conditions {#conditions}

[immunodeficiency 18](https://sugi.bio/atlas/disease/immunodeficiency-18/).

**Reported phenotype names (ClinVar):** Immunodeficiency 18, not provided, none provided, CD3-EPSILON DEFICIENCY, CD3epsilon deficiency.

## 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 2026-10-11); 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 302664). 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.*