# NM_001250.6(CD40):c.147T>C (p.Ser49=)

https://sugi.bio/variant/cd40-p-ser49

## Summary

**CD40 p.Ser49= (c.147T>C)** is classified **Benign/Likely benign** in CD40 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-20). Rare (popmax 0.125%, sas).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs541686651 · 2 submitters · rare (popmax 0.125%, sas)

## For patients & families {#patients}

This is a change in the CD40 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters.

*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.Ser49= |
| Coding change (HGVS c.) | c.147T>C |
| MANE Select transcript | [NM_001250](https://www.ncbi.nlm.nih.gov/nuccore/NM_001250) |
| dbSNP | [rs541686651](https://www.ncbi.nlm.nih.gov/snp/rs541686651/) |
| Variant type | single nucleotide variant |
| Location | chr20:46122249-46122249 (GRCh38) |
| ClinVar | [VCV1586111](https://www.ncbi.nlm.nih.gov/clinvar/variation/1586111/) |

**All HGVS expressions:** `LRG_40:g.8983T>C`, `NC_000020.10:g.44750888T>C`, `NC_000020.11:g.46122249T>C`, `NG_007279.1:g.8983T>C`, `NM_001250.6:c.147T>C`, `NM_001302753.2:c.147T>C`, `NM_001322421.2:c.147T>C`, `NM_001322422.2:c.147T>C`, `NM_001362758.2:c.147T>C`, `NM_152854.4:c.147T>C`, `NR_126502.2:n.177T>C`, `NR_136327.2:n.177T>C`

## 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 **donor loss** (Δ 0.33) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -6.036, GERP -3.15 — fast-evolving / accelerated position
- CADD: **PHRED 0.636**. 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 **0.00**, donor loss **0.33**, acceptor gain **0.21**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.33**, acceptor gain **0.21**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.125%** (sas) · FAF95 0.106% · FAF99 0.0994% · 114/91,078 in the highest group · 122/1,614,110 alleles overall — rare (popmax 0.125%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.125% | 799 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,813 |

*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 **49** lies in a disulfide bond; a β-strand.

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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-20.

**Submitter consensus:** conflicting (1 Benign, 1 Likely benign).

**Submission history:** 2 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-20 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-04-21 |

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

## Similar variants {#similar}

Related CD40 variant pages (same residue, condition, or type): [CD40 p.Ser49Asn](/variant/cd40-p-ser49asn), [CD40 c.256+5G>A](/variant/cd40-c-256-plus-5g-a), [CD40 c.*178G>A](/variant/cd40-c-star-178g-a), [CD40 c.*547A>T](/variant/cd40-c-star-547a-t), [CD40 p.Ala25Ser](/variant/cd40-p-ala25ser), [CD40 p.Arg123His](/variant/cd40-p-arg123his), [CD40 p.Asn180Lys](/variant/cd40-p-asn180lys), [CD40 p.Glu159Lys](/variant/cd40-p-glu159lys).

### 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 1586111). 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.*