# NM_001250.6(CD40):c.750A>G (p.Pro250=)

https://sugi.bio/variant/cd40-p-pro250

## Summary

**CD40 p.Pro250= (c.750A>G)** is classified **Conflicting classifications of pathogenicity** in CD40 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-16). Ultra-rare (popmax 0.0179%, nfe); Associated with hyper-IgM syndrome type 3.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs376780996 · 4 submitters · 1 linked condition · ultra-rare (popmax 0.0179%, nfe)

## For patients & families {#patients}

This is a change in the CD40 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to hyper-IgM syndrome type 3.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010579/index) · [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.Pro250= |
| Coding change (HGVS c.) | c.750A>G |
| MANE Select transcript | [NM_001250](https://www.ncbi.nlm.nih.gov/nuccore/NM_001250) |
| dbSNP | [rs376780996](https://www.ncbi.nlm.nih.gov/snp/rs376780996/) |
| Variant type | single nucleotide variant |
| Location | chr20:46128956-46128956 (GRCh38) |
| ClinVar | [VCV618003](https://www.ncbi.nlm.nih.gov/clinvar/variation/618003/) |

**All HGVS expressions:** `LRG_40:g.15690A>G`, `LRG_40t1:c.750A>G`, `NC_000020.10:g.44757595A>G`, `NC_000020.11:g.46128956A>G`, `NG_007279.1:g.15690A>G`, `NM_001250.6:c.750A>G`, `NM_001302753.2:c.*76A>G`, `NM_001322421.2:c.762A>G`, `NM_001322422.2:c.594A>G`, `NM_001362758.2:c.*76A>G`, `NM_152854.4:c.*76A>G`, `NR_126502.2:n.783A>G`, `NR_136327.2:n.686A>G`

## 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 -4.607, GERP -3.97 — fast-evolving / accelerated position
- CADD: **PHRED 1.747**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.27 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0179%** (nfe) · FAF95 0.0159% · FAF99 0.0151% · 211/1,180,042 in the highest group · 243/1,614,128 alleles overall — ultra-rare (popmax 0.0179%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0406% | 2,463 |
| European (non-Finnish) (grpmax) | 0.0179% | 5,593 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,622 |
| African / African-American | 0.00267% | 37,472 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **250** lies 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.Pro250= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-16.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2017-07-03 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-16 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-14 |

## Associated conditions {#conditions}

[hyper-IgM syndrome type 3](https://sugi.bio/atlas/disease/hyper-igm-syndrome-type-3/).

**Reported phenotype names (ClinVar):** Hyper-IgM syndrome type 3, not provided, not specified, AllHighlyPenetrant, none provided, Hyper-IgM Immunodeficiency Syndrome, Type 3.

## Similar variants {#similar}

Related CD40 variant pages (same residue, condition, or type): [CD40 c.*178G>A](/variant/cd40-c-star-178g-a), [CD40 c.*547A>T](/variant/cd40-c-star-547a-t), [CD40 c.403+20A>G](/variant/cd40-c-403-plus-20a-g), [CD40 c.52-15C>T](/variant/cd40-c-52-minus-15c-t), [CD40 c.559+36G>C](/variant/cd40-c-559-plus-36g-c), [CD40 c.-1T>C](/variant/cd40-c-minus-1t-c), [CD40 c.*135C>G](/variant/cd40-c-star-135c-g), [CD40 c.*316G>C](/variant/cd40-c-star-316g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 618003). 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.*