# NM_001242.5(CD27):c.266_267del (p.Ser89fs)

https://sugi.bio/variant/cd27-p-ser89fs

## Summary

**CD27 p.Ser89fs (c.266_267del)** is classified **Pathogenic** in CD27 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-01). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2136960831 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CD27 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD27](https://sugi.bio/atlas/gene/CD27/) |
| Protein change (HGVS p.) | p.Ser89fs |
| Coding change (HGVS c.) | c.266_267del |
| MANE Select transcript | [NM_001242](https://www.ncbi.nlm.nih.gov/nuccore/NM_001242) |
| dbSNP | [rs2136960831](https://www.ncbi.nlm.nih.gov/snp/rs2136960831/) |
| Variant type | Microsatellite |
| Location | chr12:6445551-6445552 (GRCh38) |
| ClinVar | [VCV1701181](https://www.ncbi.nlm.nih.gov/clinvar/variation/1701181/) |

**All HGVS expressions:** `LRG_357:g.5667CT[1]`, `NC_000012.11:g.6554717CT[1]`, `NC_000012.12:g.6445551CT[1]`, `NG_031995.1:g.5667CT[1]`, `NM_001242.5:c.266_267del`

## 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 4.445, GERP 1.31, phastCons 0.999 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.946, pLI 0.00016116. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 6**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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}

**CD27** population constraint: LOEUF 0.946, pLI 0.00016116, missense-Z 0.88168; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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):

- **lymphoproliferative syndrome 2** — Definitive (AR)

## Protein context {#protein}

Residue **89** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 71.79, 42% of residues very-high.

**5 experimental structure(s)** (PDB): [5TL5](https://www.rcsb.org/structure/5TL5), [5TLJ](https://www.rcsb.org/structure/5TLJ), [5TLK](https://www.rcsb.org/structure/5TLK), [7KX0](https://www.rcsb.org/structure/7KX0), [8DS5](https://www.rcsb.org/structure/8DS5).

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

*Describes the biological roles of CD27 (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:** CD27's established molecular role includes transmembrane signaling receptor activity.


### Pathways affected {#pathways}

CD27 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:** transmembrane signaling receptor activity, cysteine-type endopeptidase inhibitor activity involved in apoptotic process.

**Biological process:** T cell activation, negative regulation of apoptotic process, adaptive immune memory response involving T cells and B cells, extrinsic apoptotic signaling pathway, CD27 signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-01 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related CD27 variant pages (same residue, condition, or type): [CD27 p.Glu241del](/variant/cd27-p-glu241del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1701181). 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.*