# NM_000074.3(CD40LG):c.189del (p.Phe63fs)

https://sugi.bio/variant/cd40lg-p-phe63fs

## Summary

**CD40LG p.Phe63fs (c.189del)** is classified **Likely pathogenic** in CD40LG (ClinVar, Single submitter, 1 submitter; last evaluated 2011-08-18). No gnomAD frequency available for this variant; Associated with hyper-IgM syndrome type 1.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs193922134 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CD40LG gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to hyper-IgM syndrome type 1.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000073/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD40LG](https://sugi.bio/atlas/gene/CD40LG/) |
| Protein change (HGVS p.) | p.Phe63fs |
| Coding change (HGVS c.) | c.189del |
| MANE Select transcript | [NM_000074](https://www.ncbi.nlm.nih.gov/nuccore/NM_000074) |
| dbSNP | [rs193922134](https://www.ncbi.nlm.nih.gov/snp/rs193922134/) |
| Variant type | Deletion |
| Location | chrX:136650295-136650295 (GRCh38) |
| ClinVar | [VCV35811](https://www.ncbi.nlm.nih.gov/clinvar/variation/35811/) |

**All HGVS expressions:** `LRG_141:g.7122del`, `NC_000023.10:g.135732457del`, `NC_000023.11:g.136650298del`, `NG_007280.1:g.7122del`, `NM_000074.2:c.189delT`, `NM_000074.3:c.189del`

## 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 8.808, GERP 1.79, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 5**, so the transcript is predicted to undergo NMD.
- 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}

**CD40LG** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (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):

- **hyper-IgM syndrome type 1** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.34, 55% of residues very-high.

**8 experimental structure(s)** (PDB): [1ALY](https://www.rcsb.org/structure/1ALY), [1I9R](https://www.rcsb.org/structure/1I9R), [3LKJ](https://www.rcsb.org/structure/3LKJ), [3QD6](https://www.rcsb.org/structure/3QD6), [6BRB](https://www.rcsb.org/structure/6BRB), [6W9G](https://www.rcsb.org/structure/6W9G) — incl. mutant structure 7SGM.

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

*Describes the biological roles of CD40LG (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:** CD40LG's established molecular role includes cytokine activity.


### Pathways affected {#pathways}

CD40LG participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |
| [TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway](https://reactome.org/content/detail/R-HSA-5676594) | curated |
| [TNFR2 non-canonical NF-kB pathway](https://reactome.org/content/detail/R-HSA-5668541) | curated |
| [Affinity selection of immunoglobulins](https://reactome.org/content/detail/R-HSA-9938027) | electronic |

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

**Molecular function:** cytokine activity, CD40 receptor binding, integrin binding, protein serine/threonine kinase activator activity.

**Biological process:** inflammatory response, integrin-mediated signaling pathway, CD40 signaling pathway, platelet activation, positive regulation of interleukin-10 production, positive regulation of interleukin-12 production.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2011-08-18.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | curation | 2011-08-18 |

## Associated conditions {#conditions}

[hyper-IgM syndrome type 1](https://sugi.bio/atlas/disease/hyper-igm-syndrome-type-1/).

**Reported phenotype names (ClinVar):** Hyper-IgM syndrome type 1, Hyper-IgM Immunodeficiency Syndrome, Type 1, CD40 Ligand Deficiency, Immunodeficiency, X-linked, with hyper-IgM, X-linked hyper-IgM syndrome.

## Similar variants {#similar}

Related CD40LG variant pages (same residue, condition, or type): [CD40LG p.Ala187fs](/variant/cd40lg-p-ala187fs), [CD40LG c.288+20del](/variant/cd40lg-c-288-plus-20del), [CD40LG c.349_409+2del](/variant/cd40lg-c-349-409-plus-2del), [CD40LG c.409+1del](/variant/cd40lg-c-409-plus-1del), [CD40LG p.Ala215fs](/variant/cd40lg-p-ala215fs), [CD40LG p.Asn157fs](/variant/cd40lg-p-asn157fs), [CD40LG p.Gln114fs](/variant/cd40lg-p-gln114fs), [CD40LG p.Glu129fs](/variant/cd40lg-p-glu129fs).

### 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 35811). 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.*