Is CD40 p.Pro250= (c.750A>G) pathogenic?

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.

What condition is associated with CD40 p.Pro250= (c.750A>G)?

CD40 p.Pro250= (c.750A>G) is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 p.Pro250= (c.750A>G) in the general population?

CD40 p.Pro250= (c.750A>G) is ultra-rare (popmax 0.0179%, nfe) (gnomAD).

CD40 p.Pro250=

c.750A>G · rs376780996 · VCV618003

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, nfe)

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.27	benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.6	GERP -4
Overall
CADD	1.747	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0179% European (non-Finnish) · 211/1,180,042 alleles

Filtering AF 0.0159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0151% 243/1,614,128 alleles · ultra-rare exomes 223/1,461,882 · genomes 20/152,246 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0406%	2,463
European (non-Finnish)grpmax	0.0179%	5,593
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00267%	37,472

Finnish 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.Pro250=
Coding: c.750A>G
MANE Select: NM_001250
dbSNP: rs376780996
Type: single nucleotide variant
Location: chr20:46128956 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB
Residue 250: the 'disordered' region

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.-1T>C Benign/Likely benign ★★ same condition
CD40 c.*135C>G Benign ★★ same condition
CD40 c.*316G>C 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-pro250 (accessed [today's date]).

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