# NM_001242.5(CD27):c.334T>C (p.Cys112Arg)

https://sugi.bio/variant/cd27-p-cys112arg

## Summary

**CD27 p.Cys112Arg (c.334T>C)** is classified **Uncertain significance** in CD27 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.9505); Very rare (popmax 6.84e-05%); Associated with lymphoproliferative syndrome 2.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 6.84e-05%)

## For patients & families {#patients}

This is a change in the CD27 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Cys112Arg |
| Coding change (HGVS c.) | c.334T>C |
| MANE Select transcript | [NM_001242](https://www.ncbi.nlm.nih.gov/nuccore/NM_001242) |
| Variant type | single nucleotide variant |
| Location | chr12:6450238-6450238 (GRCh38) |
| ClinVar | [VCV4751904](https://www.ncbi.nlm.nih.gov/clinvar/variation/4751904/) |

**All HGVS expressions:** `LRG_357:g.10354T>C`, `LRG_357t1:c.334T>C`, `NC_000012.11:g.6559404T>C`, `NC_000012.12:g.6450238T>C`, `NG_031995.1:g.10354T>C`, `NM_001242.5:c.334T>C`, `NM_001413263.1:c.427T>C`, `NM_001413264.1:c.307T>C`, `NM_001413265.1:c.269-303T>C`, `NM_001413266.1:c.-117T>C`, `NM_001413267.1:c.-117T>C`, `NM_001413268.1:c.-117T>C`, `NR_182125.1:n.480T>C`, `NR_182126.1:n.480T>C`, `NR_182127.1:n.462T>C`, `NR_182128.1:n.475T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9505)
- REVEL 0.372 (indeterminate)
- SaProt LLR -12.289 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.7, GERP 0.989, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in CD27 (of 1,521 modeled).
- CADD: **PHRED 25.3**. 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.*
- Regional missense constraint: **o/e 0.90** across the covering region of the MANE Select transcript (6,445,096–6,451,389), spanning 6,293 bp. Chi-square p 0.069. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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): global (via dbSNP) **6.84e-05%** · 1/1,461,582 alleles overall — very rare (popmax 6.84e-05%).

*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 **112** lies in a disulfide bond; 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related CD27 variant pages (same residue, condition, or type): [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), [CD27 p.Arg238Lys](/variant/cd27-p-arg238lys).

### 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 4751904). 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.*