Is CD40 p.Ter278AlaextTer? (c.832_*1del) pathogenic?

CD40 p.Ter278AlaextTer? (c.8321del) is classified Likely pathogenic in CD40 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-15). Very rare (popmax 8.47e-05%, nfe); Associated with hyper-IgM syndrome type 3.

What condition is associated with CD40 p.Ter278AlaextTer? (c.832_*1del)?

CD40 p.Ter278AlaextTer? (c.832_*1del) is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 p.Ter278AlaextTer? (c.832_*1del) in the general population?

CD40 p.Ter278AlaextTer? (c.832_*1del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CD40 p.Ter278AlaextTer?

c.832_*1del · rs2515729824 · VCV2138351

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	stop-loss	predicted loss-of-function
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.6	GERP -2.7, phastCons 0.99

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 0.000137% 2/1,461,760 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	8.47e-05%	1,180,030

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CD40
Protein: p.Ter278AlaextTer?
Coding: c.832_*1del
MANE Select: NM_001250
dbSNP: rs2515729824
Type: Deletion
Location: chr20:46129036 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB

Full CD40 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyper-IgM syndrome type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CD40 c.*178G>A Uncertain significance ★★ same condition
CD40 c.*547A>T Uncertain significance ★★ same condition
CD40 c.403+20A>G Benign/Likely benign ★★ same condition
CD40 c.52-15C>T Benign/Likely benign ★★ same condition
CD40 c.559+36G>C Benign ★★ same condition
CD40 c.647-3dup Benign ★★ same condition
CD40 c.-1T>C Benign/Likely benign ★★ same condition
CD40 c.*135C>G Benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cd40-p-ter278alaextter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown