# NM_198053.3(CD247):c.300G>A (p.Pro100=)

https://sugi.bio/variant/cd247-p-pro100

## Summary

**CD247 p.Pro100= (c.300G>A)** is classified **Uncertain significance** in CD247 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-15). Ultra-rare (popmax 0.0267%, amr); Associated with immunodeficiency 25.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs541120315 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0267%, amr)

## For patients & families {#patients}

This is a change in the CD247 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Pro100= |
| Coding change (HGVS c.) | c.300G>A |
| MANE Select transcript | [NM_198053](https://www.ncbi.nlm.nih.gov/nuccore/NM_198053) |
| dbSNP | [rs541120315](https://www.ncbi.nlm.nih.gov/snp/rs541120315/) |
| Variant type | single nucleotide variant |
| Location | chr1:167438570-167438570 (GRCh38) |
| ClinVar | [VCV952188](https://www.ncbi.nlm.nih.gov/clinvar/variation/952188/) |

**All HGVS expressions:** `LRG_36:g.85040G>A`, `LRG_36t1:c.300G>A`, `NC_000001.10:g.167407807C>T`, `NC_000001.11:g.167438570C>T`, `NG_007384.1:g.85040G>A`, `NM_000734.4:c.300G>A`, `NM_001378515.1:c.393G>A`, `NM_001378516.1:c.393G>A`, `NM_198053.3:c.300G>A`

## 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 loss** (Δ 0.77) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.741, GERP 1.5, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.3**. 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 **0.77**, acceptor gain **0.00**, donor gain **0.03**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.03**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.70** (loss), gain 0.01 / loss 0.70. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0267%** (amr) · FAF95 0.0166% · FAF99 0.0136% · 16/60,022 in the highest group · 42/1,612,082 alleles overall — ultra-rare (popmax 0.0267%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0267% | 3,751 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,219 |
| European (non-Finnish) | 0.00187% | 53,552 |
| African / African-American | 0.00133% | 74,986 |
| South Asian | 0.0011% | 91,044 |

*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 **100** lies in the itam 2 domain; the 'disordered' region.

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.Pro100= falls in the itam 2 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-15.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 not provided).

**Submission history:** 2 submissions (2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-15 |
| GenomeConnect - Invitae Patient Insights Network | not provided | no classification provided | phenotyping only |  |

## 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 2026-10-14); 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 2026-10-14); 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 952188). 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.*