# NM_001250.6(CD40):c.408A>T (p.Thr136=)

https://sugi.bio/variant/cd40-p-thr136

## Summary

**CD40 p.Thr136= (c.408A>T)** is classified **Pathogenic** in CD40 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2001-10-23). Absent from gnomAD v4.1; Associated with hyper-IgM syndrome type 3.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs2145595063 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CD40 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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.Thr136= |
| Coding change (HGVS c.) | c.408A>T |
| MANE Select transcript | [NM_001250](https://www.ncbi.nlm.nih.gov/nuccore/NM_001250) |
| dbSNP | [rs2145595063](https://www.ncbi.nlm.nih.gov/snp/rs2145595063/) |
| Variant type | single nucleotide variant |
| Location | chr20:46123130-46123130 (GRCh38) |
| ClinVar | [VCV17748](https://www.ncbi.nlm.nih.gov/clinvar/variation/17748/) |

**All HGVS expressions:** `LRG_40:g.9864A>T`, `NC_000020.10:g.44751769A>T`, `NC_000020.11:g.46123130A>T`, `NG_007279.1:g.9864A>T`, `NM_001250.6:c.408A>T`, `NM_001302753.2:c.408A>T`, `NM_001322421.2:c.408A>T`, `NM_001322422.2:c.403+374A>T`, `NM_001362758.2:c.408A>T`, `NM_152854.4:c.408A>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.34) — consistent with the pathogenic call
- Conservation: phyloP 1.14, GERP 0.005, phastCons 0.069 — weakly conserved position
- CADD: **PHRED 4.328**. 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 deltas (raw): acceptor loss **0.34**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.34**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.27** (loss), gain 0.00 / loss 0.27. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2001-10-23.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2001-10-23 |

## 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, Hyper-IgM Immunodeficiency Syndrome, Type 3.

## Similar variants {#similar}

Related CD40 variant pages (same residue, condition, or type): [CD40 p.Thr136Ala](/variant/cd40-p-thr136ala), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 17748). 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.*