# NM_000732.6(CD3D):c.213T>C (p.Tyr71=)

https://sugi.bio/variant/cd3d-p-tyr71

## Summary

**CD3D p.Tyr71= (c.213T>C)** is classified **Likely benign** in CD3D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). Very rare (popmax 0.00133%, afr); Associated with immunodeficiency 19.

**At a glance:** Likely benign · review: Single submitter · rsID rs1948289381 · 1 submitter · 1 linked condition · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the CD3D gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to immunodeficiency 19.

*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 | CD3D 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/0018296/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD3D](https://sugi.bio/atlas/gene/CD3D/) |
| Protein change (HGVS p.) | p.Tyr71= |
| Coding change (HGVS c.) | c.213T>C |
| MANE Select transcript | [NM_000732](https://www.ncbi.nlm.nih.gov/nuccore/NM_000732) |
| dbSNP | [rs1948289381](https://www.ncbi.nlm.nih.gov/snp/rs1948289381/) |
| Variant type | single nucleotide variant |
| Location | chr11:118340436-118340436 (GRCh38) |
| ClinVar | [VCV2173729](https://www.ncbi.nlm.nih.gov/clinvar/variation/2173729/) |

**All HGVS expressions:** `LRG_37:g.7309T>C`, `LRG_37t1:c.213T>C`, `LRG_39:g.1093A>G`, `NC_000011.10:g.118340436A>G`, `NC_000011.9:g.118211151A>G`, `NG_007566.1:g.1093A>G`, `NG_009891.1:g.7309T>C`, `NM_000732.6:c.213T>C`, `NM_001040651.2:c.213T>C`

## 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 gain** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.472, GERP -1.58, phastCons 0.172 — weakly conserved position
- CADD: **PHRED 7.233**. 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 **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.20**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.20**.
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/74,960 in the highest group · 1/1,461,868 alleles overall — very rare (popmax 0.00133%, afr).

*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}

**CD3D** population constraint: LOEUF 1.325, pLI 1.9408e-07, missense-Z 0.44866; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (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 19** — Definitive (AR)

## Protein context {#protein}

Residue **71** lies in a disulfide bond; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 77.57, 39% of residues very-high.

**31 experimental structure(s)** (PDB): [1XIW](https://www.rcsb.org/structure/1XIW), [6JXR](https://www.rcsb.org/structure/6JXR), [7FJD](https://www.rcsb.org/structure/7FJD), [7FJE](https://www.rcsb.org/structure/7FJE), [7FJF](https://www.rcsb.org/structure/7FJF), [7PHR](https://www.rcsb.org/structure/7PHR).

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

*Describes the biological roles of CD3D (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:** CD3D's established molecular role includes identical protein binding.


### Pathways affected {#pathways}

CD3D participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [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:** identical protein binding.

**Biological process:** T cell receptor signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-01 |

## Associated conditions {#conditions}

[immunodeficiency 19](https://sugi.bio/atlas/disease/immunodeficiency-19/).

**Reported phenotype names (ClinVar):** Immunodeficiency 19, CD3-DELTA DEFICIENCY, SEVERE COMBINED IMMUNODEFICIENCY, T CELL-NEGATIVE, B CELL-POSITIVE, NK CELL-POSITIVE, SCID, T CELL-NEGATIVE, B CELL-POSITIVE, NK CELL-POSITIVE, IMMUNODEFICIENCY 19, SEVERE COMBINED.

## Similar variants {#similar}

Related CD3D variant pages (same residue, condition, or type): [CD3D p.Tyr71His](/variant/cd3d-p-tyr71his), [CD3D c.274+5G>A](/variant/cd3d-c-274-plus-5g-a), [CD3D c.407-2A>G](/variant/cd3d-c-407-minus-2a-g), [CD3D p.Arg68Ter](/variant/cd3d-p-arg68ter), [CD3D p.Cys93Ter](/variant/cd3d-p-cys93ter), [CD3D c.274+4C>T](/variant/cd3d-c-274-plus-4c-t), [CD3D c.450+6C>T](/variant/cd3d-c-450-plus-6c-t), [CD3D p.Ala119Asp](/variant/cd3d-p-ala119asp).

### 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 2173729). 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.*