# NM_198053.3(CD247):c.225C>T (p.Leu75=)

https://sugi.bio/variant/cd247-p-leu75

## Summary

**CD247 p.Leu75= (c.225C>T)** is classified **Likely benign** in CD247 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). Very rare (popmax 8.48e-05%, nfe); Associated with immunodeficiency 25.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the CD247 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to immunodeficiency 25.

*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 | CD247 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/0018294/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD247](https://sugi.bio/atlas/gene/CD247/) |
| Protein change (HGVS p.) | p.Leu75= |
| Coding change (HGVS c.) | c.225C>T |
| MANE Select transcript | [NM_198053](https://www.ncbi.nlm.nih.gov/nuccore/NM_198053) |
| Variant type | single nucleotide variant |
| Location | chr1:167438645-167438645 (GRCh38) |
| ClinVar | [VCV4708915](https://www.ncbi.nlm.nih.gov/clinvar/variation/4708915/) |

**All HGVS expressions:** `LRG_36:g.84965C>T`, `LRG_36t1:c.225C>T`, `NC_000001.10:g.167407882G>A`, `NC_000001.11:g.167438645G>A`, `NG_007384.1:g.84965C>T`, `NM_000734.4:c.225C>T`, `NM_001378515.1:c.318C>T`, `NM_001378516.1:c.318C>T`, `NM_198053.3:c.225C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 3.939, GERP -1.64, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.43**. 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: **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 **8.48e-05%** (nfe) · 1/1,179,282 in the highest group · 1/1,461,060 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}

**CD247** population constraint: LOEUF 0.633, pLI 0.65538, missense-Z 0.37572. *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 25** — Definitive (AR)

## Protein context {#protein}

Residue **75** lies in an α-helix; the itam 1 domain.

AlphaFold model confidence (whole protein): pLDDT 62.36, 8% of residues very-high.

**38 experimental structure(s)** (PDB): [1TCE](https://www.rcsb.org/structure/1TCE), [1YGR](https://www.rcsb.org/structure/1YGR), [2HAC](https://www.rcsb.org/structure/2HAC), [2OQ1](https://www.rcsb.org/structure/2OQ1), [3IK5](https://www.rcsb.org/structure/3IK5), [3IOZ](https://www.rcsb.org/structure/3IOZ).

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

*Describes the biological roles of CD247 (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:** CD247's established molecular role includes protein-macromolecule adaptor activity. p.Leu75= falls in the itam 1 domain. In Reactome, CD247 is annotated in disease pathway(s) including **FCGR3A-mediated IL10 synthesis**, **FCGR3A-mediated phagocytosis**.

**Disease mechanism (Reactome):** CD247 loss or alteration is curated in [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323), [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422), [Nef and signal transduction](https://reactome.org/content/detail/R-HSA-164944).

### Pathways affected {#pathways}

CD247 participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | other |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | other |
| ⚕ [Nef and signal transduction](https://reactome.org/content/detail/R-HSA-164944) | other |
| [Co-inhibition by PD-1](https://reactome.org/content/detail/R-HSA-389948) | other |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | other |
| [FCGR activation](https://reactome.org/content/detail/R-HSA-2029481) | other |
| [Generation of second messenger molecules](https://reactome.org/content/detail/R-HSA-202433) | other |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | other |
| [Phosphorylation of CD3 and TCR zeta chains](https://reactome.org/content/detail/R-HSA-202427) | other |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | other |
| [Role of phospholipids in phagocytosis](https://reactome.org/content/detail/R-HSA-2029485) | other |
| [Translocation of ZAP-70 to Immunological synapse](https://reactome.org/content/detail/R-HSA-202430) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein-macromolecule adaptor activity, identical protein binding, protein homodimerization activity, protein heterodimerization activity, protein tyrosine kinase binding.

**Biological process:** Fc-gamma receptor signaling pathway, T cell receptor signaling pathway, protein complex oligomerization, protein-containing complex assembly.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-23.

**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 | 2025-12-23 |

## Associated conditions {#conditions}

[immunodeficiency 25](https://sugi.bio/atlas/disease/immunodeficiency-25/).

**Reported phenotype names (ClinVar):** Immunodeficiency 25, Immunodeficiency due to defect in cd3-zeta, somatic.

## Similar variants {#similar}

Related CD247 variant pages (same residue, condition, or type): [CD247 p.Gln101Ter](/variant/cd247-p-gln101ter), [CD247 c.58+6G>T](/variant/cd247-c-58-plus-6g-t), [CD247 p.Ala120Val](/variant/cd247-p-ala120val), [CD247 p.Ala63Pro](/variant/cd247-p-ala63pro), [CD247 p.Ala9Thr](/variant/cd247-p-ala9thr), [CD247 p.Arg103Lys](/variant/cd247-p-arg103lys), [CD247 p.Arg132Cys](/variant/cd247-p-arg132cys), [CD247 p.Arg132His](/variant/cd247-p-arg132his).

### 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 4708915). 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.*