# NM_001242.5(CD27):c.261T>C (p.Cys87=)

https://sugi.bio/variant/cd27-p-cys87

## Summary

**CD27 p.Cys87= (c.261T>C)** is classified **Likely benign** in CD27 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-16). Very rare (popmax 0.00246%, nfe); Associated with lymphoproliferative syndrome 2.

**At a glance:** Likely benign · review: Single submitter · rsID rs377402413 · 1 submitter · 1 linked condition · very rare (popmax 0.00246%, nfe)

## For patients & families {#patients}

This is a change in the CD27 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to lymphoproliferative syndrome 2.

*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) | Adolescent, Adult, Childhood, Infancy |
| Diagnostic panels | CD27 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024968/index) · [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.Cys87= |
| Coding change (HGVS c.) | c.261T>C |
| MANE Select transcript | [NM_001242](https://www.ncbi.nlm.nih.gov/nuccore/NM_001242) |
| dbSNP | [rs377402413](https://www.ncbi.nlm.nih.gov/snp/rs377402413/) |
| Variant type | single nucleotide variant |
| Location | chr12:6445548-6445548 (GRCh38) |
| ClinVar | [VCV1543298](https://www.ncbi.nlm.nih.gov/clinvar/variation/1543298/) |

**All HGVS expressions:** `LRG_357:g.5664T>C`, `NC_000012.11:g.6554714T>C`, `NC_000012.12:g.6445548T>C`, `NG_031995.1:g.5664T>C`, `NM_001242.5:c.261T>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 (below), not from a missing predictor score.
- Conservation: phyloP -0.87, GERP -2.62, phastCons 0.006 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 10.26**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.22 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00246%** (nfe) · FAF95 0.00172% · FAF99 0.00149% · 29/1,179,980 in the highest group · 29/1,461,262 alleles overall — very rare (popmax 0.00246%, 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}

**CD27** population constraint: LOEUF 0.946, pLI 0.00016116, missense-Z 0.88168; 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):

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

## Protein context {#protein}

Residue **87** lies in a disulfide bond.

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-16.

**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 | 2025-02-16 |

## Associated conditions {#conditions}

[lymphoproliferative syndrome 2](https://sugi.bio/atlas/disease/lymphoproliferative-syndrome-2/).

**Reported phenotype names (ClinVar):** Lymphoproliferative syndrome 2, CD27 DEFICIENCY, Combined immunodeficiency due to CD27 deficiency.

## Similar variants {#similar}

Related CD27 variant pages (same residue, condition, or type): [CD27 p.Cys87Tyr](/variant/cd27-p-cys87tyr), [CD27 p.Cys53Tyr](/variant/cd27-p-cys53tyr), [CD27 p.Ala164Pro](/variant/cd27-p-ala164pro), [CD27 p.Ala229Thr](/variant/cd27-p-ala229thr), [CD27 p.Arg155Thr](/variant/cd27-p-arg155thr), [CD27 p.Arg172Gln](/variant/cd27-p-arg172gln), [CD27 p.Arg172Gly](/variant/cd27-p-arg172gly), [CD27 p.Arg182Ser](/variant/cd27-p-arg182ser).

### 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 2026-07-14); 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 1543298). 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.*