# NM_001252.5(CD70):c.250del (p.Ser84fs)

https://sugi.bio/variant/cd70-p-ser84fs

## Summary

**CD70 p.Ser84fs (c.250del)** is classified **Pathogenic** in CD70 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-01-10). No gnomAD frequency available for this variant; Associated with severe combined immunodeficiency due to CD70 deficiency.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1568431262 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CD70 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to severe combined immunodeficiency due to CD70 deficiency.

*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) | Childhood, Infancy |
| Diagnostic panels | CD70 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017978/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD70](https://sugi.bio/atlas/gene/CD70/) |
| Protein change (HGVS p.) | p.Ser84fs |
| Coding change (HGVS c.) | c.250del |
| MANE Select transcript | [NM_001252](https://www.ncbi.nlm.nih.gov/nuccore/NM_001252) |
| dbSNP | [rs1568431262](https://www.ncbi.nlm.nih.gov/snp/rs1568431262/) |
| Variant type | Deletion |
| Location | chr19:6586352-6586352 (GRCh38) |
| ClinVar | [VCV599338](https://www.ncbi.nlm.nih.gov/clinvar/variation/599338/) |

**All HGVS expressions:** `NC_000019.10:g.6586352del`, `NC_000019.9:g.6586363del`, `NM_001252.5:c.250del`, `NM_001330332.2:c.250del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 8.16, GERP 1.41, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.251, pLI 0.0036492. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (3 of 3)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CD70** population constraint: LOEUF 1.251, pLI 0.0036492, missense-Z 0.79554. *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):

- **severe combined immunodeficiency due to CD70 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **84** lies in the thd domain.

AlphaFold model confidence (whole protein): pLDDT 83.52, 55% of residues very-high.

**1 experimental structure(s)** (PDB): [7KX0](https://www.rcsb.org/structure/7KX0).

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

*Describes the biological roles of CD70 (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:** CD70's established molecular role includes receptor ligand activity. p.Ser84fs falls in the thd domain.


### Pathways affected {#pathways}

CD70 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [TNFs bind their physiological receptors](https://reactome.org/content/detail/R-HSA-5669034) | curated |

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

**Molecular function:** receptor ligand activity.

**Biological process:** T cell mediated immunity, B cell mediated immunity, B cell proliferation, T cell activation, adaptive immune memory response involving T cells and B cells, extrinsic apoptotic signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-01-10.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2019-01-10 |

## Associated conditions {#conditions}

[severe combined immunodeficiency due to CD70 deficiency](https://sugi.bio/atlas/disease/severe-combined-immunodeficiency-due-to-cd70-deficiency/).

**Reported phenotype names (ClinVar):** Severe combined immunodeficiency due to CD70 deficiency, CD70 DEFICIENCY, LYMPHOPROLIFERATIVE SYNDROME 3.

## Similar variants {#similar}

Related CD70 variant pages (same residue, condition, or type): [CD70 p.Arg179Ter](/variant/cd70-p-arg179ter), [CD70 p.Phe186del](/variant/cd70-p-phe186del), [CD70 p.Phe185fs](/variant/cd70-p-phe185fs).

### 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 599338). 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.*