# NM_001250.6(CD40):c.1del (p.Met1fs)

https://sugi.bio/variant/cd40-p-met1fs

## Summary

**CD40 p.Met1fs (c.1del)** is classified **Likely pathogenic** in CD40 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). Very rare (popmax 0.00133%, afr).

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1047077710 · 1 submitter · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the CD40 gene that is considered likely disease-causing, 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 | [CD40](https://sugi.bio/atlas/gene/CD40/) |
| Protein change (HGVS p.) | p.Met1fs |
| Coding change (HGVS c.) | c.1del |
| MANE Select transcript | [NM_001250](https://www.ncbi.nlm.nih.gov/nuccore/NM_001250) |
| dbSNP | [rs1047077710](https://www.ncbi.nlm.nih.gov/snp/rs1047077710/) |
| Variant type | Deletion |
| Location | chr20:46118344-46118344 (GRCh38) |
| ClinVar | [VCV2183112](https://www.ncbi.nlm.nih.gov/clinvar/variation/2183112/) |

**All HGVS expressions:** `LRG_40:g.5078del`, `LRG_40t1:c.1del`, `NC_000020.10:g.44746983del`, `NC_000020.11:g.46118344del`, `NG_007279.1:g.5078del`, `NG_143175.1:g.910del`, `NM_001250.6:c.1del`, `NM_001302753.2:c.1del`, `NM_001322421.2:c.1del`, `NM_001322422.2:c.1del`, `NM_001362758.2:c.1del`, `NM_152854.4:c.1del`, `NR_126502.2:n.31del`, `NR_136327.2:n.31del`

## 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 0.439, GERP -3.54, phastCons 0.996 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.677, pLI 0.030797. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 9**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 21.3**. 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.*
- 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 (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/74,928 in the highest group · 2/152,132 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 74,928 |
| European (non-Finnish) | 8.48e-05% | 1,179,473 |

*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}

**CD40** population constraint: LOEUF 0.677, pLI 0.030797, missense-Z 2.0303. *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 3** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.10, 60% of residues very-high.

**14 experimental structure(s)** (PDB): [1CZZ](https://www.rcsb.org/structure/1CZZ), [1D00](https://www.rcsb.org/structure/1D00), [1FLL](https://www.rcsb.org/structure/1FLL), [1LB6](https://www.rcsb.org/structure/1LB6), [3QD6](https://www.rcsb.org/structure/3QD6), [5DMI](https://www.rcsb.org/structure/5DMI).

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

*Describes the biological roles of CD40 (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:** CD40's established molecular role includes enzyme binding.


### Pathways affected {#pathways}

CD40 participates in **3 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) | other |
| [TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway](https://reactome.org/content/detail/R-HSA-5676594) | other |
| [TNFR2 non-canonical NF-kB pathway](https://reactome.org/content/detail/R-HSA-5668541) | other |

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

**Molecular function:** enzyme binding, ubiquitin protein ligase binding, signaling receptor activity.

**Biological process:** intracellular calcium ion homeostasis, cell surface receptor signaling pathway via JAK-STAT, CD40 signaling pathway, positive regulation of canonical NF-kappaB signal transduction, positive regulation of MAPK cascade, positive regulation of blood vessel endothelial cell migration.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-22 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CD40 variant pages (same residue, condition, or type): [CD40 p.Ter278AlaextTer?](/variant/cd40-p-ter278alaextter), [CD40 p.Lys29fs](/variant/cd40-p-lys29fs), [CD40 p.Thr96fs](/variant/cd40-p-thr96fs), [CD40 c.257-17_257-14del](/variant/cd40-c-257-minus-17-257-minus-14del), [CD40 c.498-30_498-11del](/variant/cd40-c-498-minus-30-498-minus-11del), [CD40 c.646+17_646+18del](/variant/cd40-c-646-plus-17-646-plus-18del), [CD40 c.647-14_647-3del](/variant/cd40-c-647-minus-14-647-minus-3del), [CD40 c.647-16_647-3del](/variant/cd40-c-647-minus-16-647-minus-3del).

### 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 2183112). 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.*