Is CD40 c.403+20A>G pathogenic?

CD40 c.403+20A>G is classified Benign/Likely benign in CD40 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Low-frequency (popmax 2.88%, nfe); Associated with hyper-IgM syndrome type 3.

What condition is associated with CD40 c.403+20A>G?

CD40 c.403+20A>G is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 c.403+20A>G in the general population?

CD40 c.403+20A>G is low-frequency (popmax 2.88%, nfe) (gnomAD).

CD40 c.403+20A>G

rs11699100 · VCV377634

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.88%, nfe)

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +20	near-intronic (+20 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.47	GERP -3
Non-coding constraint	Z 4.96	1 kb window · o/e 0.67 · regional · uncalibrated
Overall
CADD	0.448	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.88% European (non-Finnish) · 33,982/1,179,864 alleles

Filtering AF 2.85% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.84%

Overall 2.57% 41,479/1,613,894 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	8.02%	12
European (non-Finnish)grpmax	2.88%	35
Remaining individualsnot grpmax-eligible	2.64%	38
Finnishnot grpmax-eligible	2.22%	45
Admixed American	1.29%	78
African / African-American	0.856%	117
Amishnot grpmax-eligible	0.769%	130
Middle Eastern	0.66%	152
South Asian	0.641%	156
East Asian	0.0223%	4,486

Ashkenazi Jewish 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
Coding: c.403+20A>G
MANE Select: NM_001250
dbSNP: rs11699100
Type: single nucleotide variant
Location: chr20:46122776 (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.52-15C>T Benign/Likely benign ★★ same condition
CD40 c.559+36G>C Benign ★★ same condition
CD40 c.-1T>C Benign/Likely benign ★★ same condition
CD40 c.*135C>G Benign ★★ same condition
CD40 c.*316G>C Benign ★★ same condition
CD40 p.Ala207= Benign/Likely 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-c-403-plus-20a-g (accessed [today's date]).

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