# NM_001250.6(CD40):c.678_679delinsTG (p.Pro227Ala)

https://sugi.bio/variant/cd40-p-pro227ala

## Summary

**CD40 p.Pro227Ala (c.678_679delinsTG)** is classified **Likely benign** in CD40 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-12). No gnomAD frequency available for this variant.

**At a glance:** Likely benign · review: Single submitter · rsID rs2515729134 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CD40 gene that is classified as likely benign — not considered 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.Pro227Ala |
| Coding change (HGVS c.) | c.678_679delinsTG |
| MANE Select transcript | [NM_001250](https://www.ncbi.nlm.nih.gov/nuccore/NM_001250) |
| dbSNP | [rs2515729134](https://www.ncbi.nlm.nih.gov/snp/rs2515729134/) |
| Variant type | Indel |
| Location | chr20:46128884-46128885 (GRCh38) |
| ClinVar | [VCV1993262](https://www.ncbi.nlm.nih.gov/clinvar/variation/1993262/) |

**All HGVS expressions:** `LRG_40:g.15618_15619delinsTG`, `LRG_40t1:c.678_679delCCinsTG`, `NC_000020.10:g.44757523_44757524delinsTG`, `NC_000020.11:g.46128884_46128885delinsTG`, `NG_007279.1:g.15618_15619delinsTG`, `NM_001250.6:c.678_679delinsTG`, `NM_001302753.2:c.*4_*5delinsTG`, `NM_001322421.2:c.690_691delinsTG`, `NM_001322422.2:c.522_523delinsTG`, `NM_001362758.2:c.*4_*5delinsTG`, `NM_152854.4:c.*4_*5delinsTG`, `NR_126502.2:n.711_712delinsTG`, `NR_136327.2:n.614_615delinsTG`

## 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 -0.624, GERP -3.45 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Regional missense constraint: **o/e 0.74** across the covering region of the MANE Select transcript (46,118,344–46,129,037), spanning 10,693 bp. Chi-square p 2e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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}

**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}

Residue **227** lies in a UniProt-annotated variant site (in); the 'disordered' region.

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. p.Pro227Ala falls in the disordered region.


### 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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-12.

**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 | 2022-05-12 |

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

## Similar variants {#similar}

Related CD40 variant pages (same residue, condition, or type): [CD40 p.Pro227=](/variant/cd40-p-pro227).

### 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 1993262). 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.*