Is CD40 p.Pro127= (c.381C>T) pathogenic?

CD40 p.Pro127= (c.381C>T) is classified Conflicting classifications of pathogenicity in CD40 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-18). Ultra-rare (popmax 0.0468%, eas); Associated with hyper-IgM syndrome type 3.

What condition is associated with CD40 p.Pro127= (c.381C>T)?

CD40 p.Pro127= (c.381C>T) is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 p.Pro127= (c.381C>T) in the general population?

CD40 p.Pro127= (c.381C>T) is ultra-rare (popmax 0.0468%, eas) (gnomAD).

CD40 p.Pro127=

c.381C>T · rs763263083 · VCV496127

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -2.8
Overall
CADD	7.757	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0468% East Asian · 21/44,884 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.00353% 57/1,613,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0468%	2,137
Middle Eastern	0.0164%	6,084
African / African-American	0.00934%	10,702
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Finnishnot grpmax-eligible	0.00469%	21,333
South Asian	0.0022%	45,538
Admixed American	0.00167%	60,002
European (non-Finnish)	0.00153%	65,557

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.Pro127=
Coding: c.381C>T
MANE Select: NM_001250
dbSNP: rs763263083
Type: single nucleotide variant
Location: chr20:46122734 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB
Residue 127: a disulfide bond

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 p.Pro127Ser Uncertain significance ★ ⚠ same residue
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

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-pro127 (accessed [today's date]).

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