# NM_000733.4(CD3E):c.103C>T (p.Pro35Ser)

https://sugi.bio/variant/cd3e-p-pro35ser

## Summary

**CD3E p.Pro35Ser (c.103C>T)** is classified **Benign/Likely benign** in CD3E (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-05). AlphaMissense: likely benign (0.1224); Rare (popmax 0.18%, nfe); Associated with immunodeficiency 18.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs143949187 · 6 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.18%, nfe)

## For patients & families {#patients}

This is a change in the CD3E gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 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.Pro35Ser |
| Coding change (HGVS c.) | c.103C>T |
| MANE Select transcript | [NM_000733](https://www.ncbi.nlm.nih.gov/nuccore/NM_000733) |
| dbSNP | [rs143949187](https://www.ncbi.nlm.nih.gov/snp/rs143949187/) |
| Variant type | single nucleotide variant |
| Location | chr11:118312170-118312170 (GRCh38) |
| ClinVar | [VCV302661](https://www.ncbi.nlm.nih.gov/clinvar/variation/302661/) |

**All HGVS expressions:** `LRG_38:g.12591C>T`, `LRG_38t1:c.103C>T`, `NC_000011.10:g.118312170C>T`, `NC_000011.9:g.118182885C>T`, `NG_007383.1:g.12591C>T`, `NM_000733.4:c.103C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1224)
- REVEL 0.043 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.412 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -4.694, GERP -3.88 — fast-evolving / accelerated position
- CADD: **PHRED 0.012**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.26 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.18%** (nfe) · FAF95 0.173% · FAF99 0.171% · 2,115/1,177,500 in the highest group · 3,206/1,611,270 alleles overall — rare (popmax 0.18%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 1.37% | 73 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.318% | 315 |
| European (non-Finnish) (grpmax) | 0.18% | 557 |
| Remaining individuals (not grpmax-eligible) | 0.141% | 709 |
| Middle Eastern | 0.033% | 3,026 |
| Admixed American | 0.0267% | 3,751 |
| East Asian | 0.0134% | 7,477 |
| African / African-American | 0.012% | 8,328 |
| South Asian | 0.0022% | 45,507 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **35** lies in an α-helix; 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.Pro35Ser 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-05.

**Submitter consensus:** conflicting (4 Likely benign, 2 Benign).

**Submission history:** 6 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-05 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2023-10-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-22 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related CD3E variant pages (same residue, condition, or type): [CD3E p.Pro35=](/variant/cd3e-p-pro35), [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 2026-10-14); 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 302661). 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.*