# NM_001242.5(CD27):c.630C>A (p.Phe210Leu)

https://sugi.bio/variant/cd27-p-phe210leu

## Summary

**CD27 p.Phe210Leu (c.630C>A)** is classified **Uncertain significance** in CD27 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-29). AlphaMissense: likely pathogenic (0.6439); Very rare (popmax 8.47e-05%, nfe); Associated with lymphoproliferative syndrome 2.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## 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 |

**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.Phe210Leu |
| Coding change (HGVS c.) | c.630C>A |
| Variant type | single nucleotide variant |
| Location | chr12:6450986-6450986 (GRCh38) |
| ClinVar | [VCV3663590](https://www.ncbi.nlm.nih.gov/clinvar/variation/3663590/) |

**All HGVS expressions:** `LRG_357:g.11102C>A`, `LRG_357t1:c.630C>A`, `NC_000012.11:g.6560152C>A`, `NC_000012.12:g.6450986C>A`, `NG_031995.1:g.11102C>A`, `NG_187908.1:g.235C>A`, `NM_001242.5:c.630C>A`, `NM_001413263.1:c.723C>A`, `NM_001413264.1:c.603C>A`, `NM_001413265.1:c.450C>A`, `NM_001413266.1:c.180C>A`, `NM_001413267.1:c.180C>A`, `NM_001413268.1:c.180C>A`, `NR_015382.2:n.532G>T`, `NR_182125.1:n.776C>A`, `NR_182126.1:n.776C>A`, `NR_182127.1:n.758C>A`, `NR_182128.1:n.769C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.6439)
- REVEL 0.193 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -5.533 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 0.005, GERP -0.054, phastCons 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 14.83**. 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 looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,986 in the highest group · 1/1,461,844 alleles overall — very rare (popmax 8.47e-05%, 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.*

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-29.

**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 | 2024-11-29 |

## 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.

### 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 3663590). 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.*